Acute effects of a single intravenous injection of diazoxide on plasma glucose and lipid metabolism were investigated in 12 healthy, anesthetized dogs, each serving as its own control. The dose of diazoxide/Kg. body weight was 20 mg. in 8 dogs and 15 mg. in 4 dogs. Glucose metabolism was determined in 7 dogs using 4 successive measured injections of tracer glucose-U-C 14, and turnover rates of plasma FFA were estimated in 3 dogs using a constant intravenous infusion of trace amounts of both palmitic acid-9, 10-H 3 and linoleic acid-1-C 14, complexed with albumin. The larger dose of diazoxide evoked in all 8 dogs prompt increments in both plasma glucose and FFA concentrations, with mean ± 1 S.E. maximal increases above control values of 106 ± 30 mg. 100 ml. and 920 ± 174 μEq./L., respectively. On the other hand, plasma triglyceride and cholesterol concentrations did not change significantly for 3 3 4 hours after diazoxide administration. In keeping with the change in plasma glucose concentration, intermixing glucose mass, determined in 3 of the 8 dogs, showed an average maximal increase of 62 per cent above control after diazoxide. Rate of glucose appearance (primarily hepatic output) was increased by 42 per cent above control immediately after diazoxide but returned to control values 1 1 4 hours later. Interestingly enough, rate of glucose disappearance (tissue uptake) was not altered significantly by diazoxide despite the marked increase in plasma concentration and intermixing mass of glucose. The smaller dose of diazoxide produced in the remaining 4 dogs less pronounced alterations than the above, but the trend was similar. During simultaneous infusion of labeled palmitate and linoleate in 3 dogs, concentrations of H 3 and C 14 radio-activities of plasma FFA were slightly increased, but plasma FFA specific activities were decreased by diazoxide. Mean ± 1 S.E. turnover rates of plasma FFA during the control periods were 29.9 ± 2.4 and 27.3 ± 2.1 μEq./min. for H 3-FFA and C 14-FFA, respectively, while corresponding rates after diazoxide were 101.9 ± 29.5 and 79.2 ± 19.6 μEq./min. Finally, despite the fall in specific activities of plasma FFA which presumably would likewise affect the hepatic FFA pools that provide precursors for triglyceride synthesis, the rates of incorporation of H 3 and C 14 labeled FFA into plasma triglyceride were increased. In conclusion, diazoxide induces hyperglycemia in dogs as a result of increased hepatic glucose output and relative inhibition of glucose utilization by tissues, and it raises plasma FFA concentration by enhancing the influx of FFA into plasma.