Sixty-four patients with non-insulin-dependent diabetes mellitus were treated with a combination of insulin and oral sulfonylurea therapy in a double-blind, placebo-controlled trial during a 12-month period. Combination therapy lowered fasting glucose levels significantly only at the third and fourth months of treatment. Glycohemoglobin levels were significantly lower than control at 3 and 6 months whereas C-peptide levels were significantly increased at 3 and 9 months. Responders exhibited as much as a 50% reduction in total insulin dose compared with nonresponders or control subjects. These results suggest that combination therapy affords transient metabolic improvement in certain patients with non-insulin-dependent diabetes. Improvement in fasting glucose levels appears to be mediated by enhanced insulin secretion. Combination therapy may increase the cost of treatment by nearly 50% and appears warranted only in selected patients.