The most widely reported and, perhaps, the most effective gas of the First World War was mustard gas. It was a vesicant that was introduced by Germany in July 1917 prior to the Third Battle of Ypres. The Germans marked their shells yellow for mustard gas and green for chlorine and phosgene; hence they called the new gas Yellow Cross. It was known to the British as HS (Hun Stuff), while the French called it Yperite (named after Ypres).

Mustard gas is not a particularly effective killing agent (though in high enough doses it is fatal) but can be used to harass and disable the enemy and pollute the battlefield. Delivered in artillery shells, mustard gas was heavier than air, and it settled to the ground as an oily liquid resembling sherry. Once in the soil, mustard gas remained active for several days, weeks, or even months, depending on the weather conditions.

The skin of victims of mustard gas blistered, their eyes became very sore and they began to vomit. Mustard gas caused internal and external bleeding and attacked the bronchial tubes, stripping off the mucous membrane. This was extremely painful. Fatally injured victims sometimes took four or five weeks to die of mustard gas exposure.

One nurse, Vera Brittain, wrote: "I wish those people who talk about going on with this war whatever it costs could see the soldiers suffering from mustard gas poisoning. Great mustard-coloured blisters, blind eyes, all sticky and stuck together, always fighting for breath, with voices a mere whisper, saying that their throats are closing and they know they will choke."

The polluting nature of mustard gas meant that it was not always suitable for supporting an attack as the assaulting infantry would be exposed to the gas when they advanced. When Germany launched Operation Michael on 21 March 1918, they saturated the Flesquières salient with mustard gas instead of attacking it directly, believing that the harassing effect of the gas, coupled with threats to the salient's flanks, would make the British position untenable.

Gas never reproduced the dramatic success of 22 April 1915; however, it became a standard weapon which, combined with conventional artillery, was used to support most attacks in the later stages of the war. Gas was employed primarily on the Western Front—the static, confined trench system was ideal for achieving an effective contingent. Germany also made use of gas against Russia on the Eastern Front, where the lack of effective countermeasures resulted in deaths of over 56,000 Russians, while Britain experimented with gas in Palestine during the Second Battle of Gaza. Russia began manufacturing chlorine gas in 1916, with phosgene being produced later in the year. However, most of the manufactured gas was never used.

The British Army believed that the use of gas was needed, but did not use mustard gas until November 1917 at Cambrai, after their armies had captured a stockpile of German mustard-gas shells. It took the British more than a year to develop their own mustard gas weapon, with production of the chemicals centred on Avonmouth Docks. (The only option available to the British was the Despretz–Niemann–Guthrie process). This was used first in September 1918 during the breaking of the Hindenburg Line with the Hundred Days' Offensive.

The Allies mounted more gas attacks than the Germans in 1917 and 1918 because of a marked increase in production of gas from the Allied nations. Germany was unable to keep up with this pace despite creating various new gases for use in battle, mostly as a result of very costly methods of production. Entry into the war by the United States allowed the Allies to increase mustard gas production far more than Germany.[44] Also the prevailing wind on the Western Front was blowing from west to east, which meant the British more frequently had favorable conditions for a gas release than did the Germans.

Though the United States never used chemical weapons of its own manufacture in World War I (the Artillery used Mustard gas with significant effect during the Meuse Argonne Offensive on at least three occasions [46]), it had begun large-scale production of an improved vesicant gas known as Lewisite, for use in an offensive planned for early 1919. By the time of the armistice on 11 November, a plant near Willoughby, Ohio was producing 10 tons per day of the substance, for a total of about 150 tons. It is uncertain what effect this new chemical would have had on the battlefield, however, as it degrades in moist conditions.