Secondary failure to oral hypoglycemic agents (OHAs) is a possible outcome for non-insulin-dependent diabetes mellitus (NIDDM) patients and poses a serious therapeutic problem. In this study, we evaluated the effect of adding a single bedtime low-dose NPH insulin injection to the previous ineffective sulfonylurea therapy in 23 NIDDM patients with true secondary failure to OHAs. This treatment schedule was conducted for 3 mo by 18 patients (78%) who completed the study. In these patients, the addition of NPH insulin (0.2 +/- 0.01 IU/kg body wt) greatly decreased fasting and postprandial plasma glucose (P less than .001) and glycosylated hemoglobin (P less than .005). No weight gain was observed in any of the patients studied. Five patients dropped out: 2 patients (9%) due to insufficient compliance, 2 patients (9%) due to the multiple insulin injections required to achieve good metabolic control, and 1 patient (4%) due to recurrent hypoglycemic episodes. No correlation was observed between glucagon-stimulated C-peptide values and amelioration of metabolic control. In conclusion, most NIDDM patients with secondary failure to OHAs may be successfully treated with the addition of a single low-dose bedtime NPH insulin injection, and residual beta-cell function evaluation is not able to predict the effectiveness of the combined treatment.