Background: DDAVP tablets are more appealing than the nasal spray, which is safe and effective in the treatment of PNE. This study evaluated the safety and effectiveness of oral DDAVP in reducing the number of wet nights in children with PNE over a 14-week period. Methods: A multicenter (16) trial of oral DDAVP in children, ages 6-16 years, with PNE was conducted in 4 phases: a 2-week screening/qualifying (at least 3 wet nights per week); a 2-week, randomized, double-blind, placebo-controlled, parallel-group, dose-range; a 2-week placebo washout; and an 8-week ascending dose titration. In the dose-range phase of the study, patients were randomized to 1 of 4 treatment groups: 200, 400, 600 mcg/day of DDAVP or placebo. In the dose-titration phase of the study, patients were randomized to either 200 mcg/day of DDAVP or placebo for 2 weeks. Patients not completely dry after 2 weeks of treatment had their dose increased to 400 mcg/day for 2 weeks; if not dry after 2 weeks, the dose was increased to a maximum of 600 mcg/day for an additional 4 weeks. Placebo patients were titrated in the same manner by increasing the number of tablets. The efficacy variables were the mean reduction from baseline in the number of wet nights and the percentage of patients responding to treatment. Results: In the dose-range phase of the study, 193 patients were evaluated. All doses of DDAVP produced significantly (p<0.001) superior reductions from baseline in the number of wet nights with 27%, 30% and 40% reductions for the 200, 400 and 600 mcg/day dose groups. 14%-31%, of the patients showed an excellent response (< 2 wet nights/2 weeks) compared to 6% of the placebo patients while 5%-13% of the patients remained completely dry. In the dose-titration phase of the study, (148 patients), all of the placebo patients and 87% of the DDAVP patients had to be titrated to the maximum dose. The 200 mcg/day dose was significantly superior (p<0.05) to placebo at weeks 2 and 4 with 20% and 63% reduction in wet nights versus 9% in the placebo group. The 400 and 600 mcg/day doses produced significantly (p<0.05) superior reductions in the number of wet nights at week 8 compared to placebo; 75% and 30%, respectively, versus 18%. At the end of the 8-week titration period, 24% of the DDAVP treated patients had an excellent response versus 3% of placebo patients; 7% of DDAVP patients were completely dry while none of the placebo patients were. Conclusion: Oral DDAVP at daily dosages of 200 to 600 mcg/day significantly reduced bedwetting in enuretic children and was well tolerated for up to 8 weeks.