The authors previously demonstrated in dogs that a bolus dose of sodium thiosulfate maintained enhanced cyanide metabolism throughout a 1-h infusion of sodium nitroprusside (SNP). To further test this antidotal action, a bolus dose of thiosulfate (150 mg·kg−1) was given to eight dogs at theendof a 60-min near-lethal infusion of nitroprusside (3 mg·kg−1). Within 2 min of the antidote, mean plasma thiocyanate levels (70.3 μmol·1−1) were significantly higher than those of seven control dogs given nitroprusside only (45.9 μmol·1−1,P= 0.002) and plateaued at 153.8 μmol·1−1within 60 min, while the control values only reached 79.1 μmol·1−1(P< 0.001). Although differences between plasma cyanide levels in the two groups only attained significance 1 h after administering the antidote (0.8vs.2.74 μmol·1−1,P= 0.03), red blood cell cyanide concentrations were significantly lower in the antidote group within 5 min (166vs. 225μmol·1−1,P= 0.004) and remained so throughout the 2-h observation period. Compared with the controls, there was an impressive reduction in mean half-lives of plasma cyanide (25.1vs.74.1 min) and red blood cell cyanide (22.4vs.203.6 min). Similarly, peak cyanide levels occurred much sooner following the antidote (mean times: plasma cyanide 2.9vs.5.9 min; red blood cell cyanide 0.25vs.11 min). Whereas mean blood lactate levels remained elevated for at least 1 h after infusion in the controls, they showed a decrease within 5 min in the antidote dogs, becoming significantly lower 25 min later (P< 0.01). These results suggest that thiosulfate alone is a sufficient antidote for cyanide toxicity arising from excessive SNP administration. The data also suggest that red blood cells may be involved in the detoxication process.