The effect of iv tolbutamide on endogenous glucagon levels was measured in nine insulin-dependent diabetic patients chosen because they evidenced no C-peptide response to beta-cell secretagogues. Basal glucagon levels were not suppressed by a sustained tolbutamide infusion; in fact, a slight stimulatory effect was observed at 5, 10, 30, and 45 min. In the absence of detectable insulin secretory capacity and suboptimal insulin replacement, tolbutamide appears to be a stimulus, not a suppressant, of glucagon secretion.