Intensive insulin treatment, when combined with sulfonylurea drugs, may enhance remissions in new-onset type I diabetic patients. These clinical data suggest that sulfonylurea drugs may have immunosuppressive actions in addition to insulin secretory and sensitivity actions. Thus, studies were conducted in humans to determine if glipizide was immunomodulatory in vitro. Five, 10, and 15 micrograms/mL of phytohemagglutinin (PHA) and concanavalin A (Con A), and 0.5, 1.0, and 1.5 micrograms/mL of pokeweed mitogen (PWM) were incubated with normal human peripheral blood mononuclear cells. Maximum stimulatory indices were 52, 39, and 30 for PHA, Con A, and PWM, respectively. Additional incubations were performed in the presence of 1, 10(1), 10(2), 10(3), 10(4), and 10(5) ng/mL glipizide. Glipizide concentrations inhibiting mitogen stimulation approximately 50% (P less than .01 v nonglipizide control) were 1.0 ng/mL for PWM, 10 ng/mL for Con A, and 10(4) ng/mL for PHA. At higher glipizide levels, inhibition was 90% to 100%. To determine if glipizide immunomodulates diabetes-associated reactions, bio-breeding (BB) diabetic rat splenic macrophage-mediated islet killing was studied. Glipizide at 10(3) ng/mL inhibited islet killing by 60% (P less than .001). These preliminary data suggest that glipizide may have immunomodulatory actions not previously appreciated, and may be related to this drug's putative action in islet cell restoration.