Hormonal and glycemic changes in 22 rhesus monkeys were characterized during the first days after treatment with streptozotocin (STZ) (45 to 55 mg/kg, administered intravenously [IV]. Almost half ( 10 22 ) of the monkeys developed insulin-dependent diabetes mellitus (STZ-IDDM) within five days following injection. Four of the remaining monkeys did not become insulin dependent for at least 6 months after STZ treatment, during which time they were considered non-insulin-dependent, and eight monkeys never required exogenous insulin. In the STZ-IDDM group, plasma immunoreactive c-peptide (IRC-P) levels fell by three hours after STZ from a mean ± SEM of 252 ± 82 to 101 ± 45 pg/mL, as glucose and immunoreactive glucagon (IRG) levels increased from 65 ± 3 and 120 ± 37, respectively, to 336 ± 43 mg/dL and 234 ± 52 pg/mL, respectively. Between six and 30 hours after treatment, IRC-P increased to a peak of 1,561 ± 360 pg/mL before falling permanently to <60 pg/mL by 66 hours. During this period, glucose and IRG responded in a reciprocal fashion by falling and then increasing to levels above 300 mg/dL and 300 pl/mL, respectively, by 66 hours. In the non-insulin-dependent diabetes mellitus (STZ-NIDDM) group, no clear reciprocal relationship between IRC-P and glucose and IRG was obtained. In nine additional monkeys subjected to total pancreatectomy (Px), IRC-P and IRG levels fell immediately and permanently by >90% and 75%, respectively. Levels of immunoreactive somatostatin increased steadily over the initial 96 hours following STZ, but did so in both STZ-IDDM and Px monkey groups. Plasma lipid hydroperoxide levels measured in two monkeys that developed STZ-IDDM were unchanged during the first 96 hours after STZ administration. In conclusion, the glycemic and hormonal pattern observed with STZ-IDDM rhesus monkeys during the first days following treatment is indicative of selective pancreatic β-cell destruction resulting from a direct action of STZ.