The combination of desmopressin (DDAVP) and behavioral therapy for treatment of nocturnal enuresis was compared with use of each of these modes alone. We randomly assigned 226 enuretic children being treated in primary care clinics of a major medical center in the largest health maintenance organization in Israel into 3 groups: Group A) DDAVP plus behavioral therapy (double-blind); Group B) behavioral therapy plus placebo (double-blind); and Group C) DDAVP alone (open group). DDAVP (20 μg/naris) and placebo were administered by intranasal spray. Both pharmacologic and behavioral therapy were initiated after a 2-week observation period and continued for 8 weeks. All patients were followed for 2 months after completion of treatment. A significant reduction in the number of wet nights/week was registered for all 3 groups: 49% in Group A, 45% in Group B, and 19% in Group C. After controlling for confounding factors, no significant difference in effect was noted among the 3 types of treatment during the trial period. However, on follow-up the results for the DDAVP patients were significantly less stable compared with the other 2 groups (p=0.015). Minor side effects were registered, but none of the participants withdrew from the trial. To our knowledge, this is the largest randomized trial of nocturnal enuresis conducted to date. Our findings suggest that simply discussing the problem with the patient and family leads to improvement, and that behavioral therapy is also beneficial. DDAVP can help, but the relapse rate on discontinuation is high.