Whereas a great deal of information is available on the etiology of methanol poisoning in the monkey, very little study has been made in human subjects. The role of formic acid in methanol toxicity in human subjects has not been established. Two patients have been studied who have presented with the characteristics of methanol poisoning--metabolic acidosis and ocular toxicity. This has made possible a confirmation of the role of formate in the toxic syndrome. Acidosis was very severe in both cases with arterial pH values of about 6.9 and plasma bicarbonate concentrations of 3 meq/liter. A sensitive and specific assay was used to measure formic acid levels in blood and other fluids. Formate accumulation was marked with initial blood levels ranging from 11.1 to 26.0 meq/liter. Decreases in blood bicarbonate concentrations of similar magnitude coincided with the increase in formate. Thus, accumulation of formic acid plays a major part in the acidosis observed in human subjects poisoned with methanol, as has been demonstrated in monkeys. Treatment involving bicarbonate administration, ethanol infusion and hemodialysis, rapidly decreased formate levels in the blood to control values. Methanol concentrations were reduced but to lesser extent than that of formate. Despite the reduction in formate and methanol concentrations in both cases, the treatment was successful in only one of the two patients.