Because the belief that cyanide is released from nitroprussidein vivorecently was challenged, the authors performed a series of experiments that examined the conditions under which nitroprusside is degraded. These experiments include an examination of the release of cyanide and nitric oxide from nitroprussidein vitro, the release of cyanidein vivo, and a comparison of the biologic activity of intact and degraded nitroprusside. Nitroprusside in aqueous solution degraded when exposed to white or blue light but not to red light. While light at 20 μW·cm−2produced 40% apparent photodegradation after 6 h exposure, while white light at 220 μW·cm−2produced 100% apparent photodegradation after 2 h exposure. At 100% apparent photodegradation, 10% of the nitrosyl ligand was recovered as free nitric oxide, and 0.4% of the cyanide ligand was recovered as free cyanide. Following a 2-h infusion of light-protected nitroprusside in seven patients, cyanide concentrations ranged from 1.4 to 45.5 μM and 0.09 to 3.2 μM in blood and plasma, respectively. These values were not changed by exposing the samples to white light (220 μW·cm−2) for 4 h. Intact and photodegraded nitroprusside produced identical hypotensive responses in rats as would be expected, since the nitrosyl ligand was detected in solution following degradation, and it mediates this action. Cyanide was released from nitroprusside, both on its exposure to lightin vitroand alsoin vivo. The latter was not an artifact of the assay for cyanide. Nitroprusside releases cyanidein vivo, and cyanide toxicity is a true complication of its use.