The causes of secondary failure with tolbutamide therapy were studied in 1,965 diabetic patients. Among the 432 failures (22% of the total), 81 occurred during the first year, 162 during the second, 127 during the third, 51 during the fourth, and 11 during the fifth year of treatment. Factors considered responsible were: (1) unwise initial selection of patients, 5.6%; (2) poor diet adherence, 3.5%; (3) inadequate dosage of drug, 8.3%; and (4) temporary failure due to metabolic stress, 0.9%; which left a balance of 3.7% due to unexplained drug failure. It is concluded that true late unresponsiveness to tolbutamide is less common than has been reported by some. Furthermore, among 127 patients who resumed insulin, the requirement was equal to or lower than that before sulfonylurea treatment in 74, and in only 17 patients was it greater by 20% or more.