Thirty-nine dogs (including eight from a previous study) were given during a one-hour infusion either low (less than 1.0 mg/kg) or high doses (greater than 1.0 mg/kg) of sodium nitroprusside in the presence or absence of circulating methemoglobin. In animals given low doses, the metabolic effects were relatively mild and consistent with those accounted for by a reduction in arterial pressure to 40 torr. In animals given high doses (with the same arterial pressure), metabolic alterations were significantly magnified and oxygen extraction was decreased. Animals pretreated with methemoglobin and given high doses of nitroprusside (again at the same arterial pressure) showed no toxic effect of nitroprusside. In separate studies, blood and tissue levels of cyanide were measured in dogs given high doses of nitroprusside (2.5-3.5 mg/kg) in the presence or absence of methemoglobin. In dogs given methemoglobin, 60 per cent of the administered cyanide (as nitroprusside) was recovered in the blood (as cyanmethemoglobin) after a one-hour infusion. Thereafter, blood cyanide levels declined over three hours to 25 per cent of peak levels, presumably by conversion to thiocyanate, since tissue levels of cyanide were negligible. In dogs not given methemoglobin, blood cyanide levels qualitatively followed a similar pattern but quantitatively were a fourth to a third those of pretreated dogs, and tissue levels of cyanide became elevated. It is concluded that in the dog nitroprusside, acutely administered, causes cyanide toxicity at doses exceeding 1.0-1.5 mg/kg, that the release of cyanide from nitroprusside in blood is rapid and in large quantities, that detoxification (presumably by conversion of cyanide to thiocyanate) is likewise fairly rapid but insufficient to prevent toxicity, and that protection is provided by methemoglobin.