The .221 Fireball has had an extremely odd career. Originally introduced as a varmint cartridge for pistols, it never became popular and was eventually discontinued, only to be re-introduced as a rifle cartridge.

Remington introduced the .221 Fireball in 1963 as the sole cartridge for their new XP-100 single shot pistol. ("XP" stood for experimental pistol.) The XP-100 was based on the Model 600 bolt action rifle fitted with a 10.5" ventilated-rib barrel and a rather futuristic looking pistol grip and forearm made from Zytel Nylon. The .221 Fireball cartridge was based on a shortened .222 Remington case. Neither made much of an impact on the shooting world, although both remained in production for many years. The T/C Contender single shot pistol has also been chambered for the .221 Fireball cartridge.

The .221 is the highest velocity pistol cartridge ever loaded by a major ammunition maker. Its SAAMI maximum mean pressure is 52,000 cup, the same as for the .223 Rem. and higher than that permitted for the .222 Rem. It was intended specifically for the sport of handgun varmint hunting, and it remains perhaps the best pistol cartridge for that purpose to this day.

In recent years the .221 has also found favor with a small number of rifle shooters looking for a relatively quiet varmint cartridge for use in semi-populated areas. The Fireball offers superior performance to the .22 Hornet, its main competitor in this role. In 2002 Remington chose the .221 Fireball as the cartridge for that year's Model 700 Classic Limited Edition rifle.

Remington's .221 Fireball factory load for the XP-100 pistol, now discontinued, offered a 50 grain spitzer bullet at a muzzle velocity (MV) of 2650 fps. This made the .221/XP-100 combination the ballistic equal of a .22 Hornet varmint rifle, and about a 175 yard varmint cartridge.

In 2002 Remington re-introduced the .221 as a rifle cartridge. Their Centerfire Rifle Ballistics Table shows a 50 grain V-Max boat tail bullet at a MV of 2995 from a 24" barrel. The accompanying trajectory table shows that with a 200 yard zero that bullet hits 1.8" high at 100 yards, 1.7" high at 150 yards, and 3.4" low at 250 yards. This trajectory makes the .221 about a 225 yard varmint cartridge.

The Nosler Reloading Guide No. 5 shows that 18.0 grains of RL7 powder will drive their 50 grain Ballistic Tip bullet to a MV of 2750 fps from a 14" pistol barrel. Reloaders also have the alternative of 40, 45, 52-53, and 55 grain bullets.

In the rifle cartridge section of the Nosler Reloading Guide No. 4 it is revealed that the .221 Fireball (using their 40 grain Ballistic Tip bullet) is the favorite small varmint cartridge of the Nosler ballistics staff. 17.0 grains of RL7 powder will drive this bullet to a MV of 2869 fps, and 19.0 grains of RL7 will drive it to 3242 fps. The Nosler staff used Federal 205M primers in Remington cases to develop these loads, whch were chronographed in a 22" rifle barrel.

In either rifle or pistol the .221 is a very accurate cartridge with adequate energy for its intended purpose. With fragile varmint bullets it can deliver quick kills to its maximum point blank range.