Objective: To assess the efficacy, tolerability and side effects of the diuretic hydrochlorothiazide (HCTZ) in the management of monosymptomatic nocturnal enuresis by a placebo-controlled double-blind crossover trial. Patients and Methods: Forty patients suffering from nocturnal enuresis were blindly randomized into 2 groups of equal numbers. Group 1 first received placebo for 3 months, and group 2 received oral HCTZ once daily for the same period. Both groups, after a 2-week wash-out period, were crossed over in their medication and continued treatment for another 3 months. The main outcome measure (variable) for the assessment of drug efficacy was taken to represent the average reduction in the percentage of wet nights as compared to the baseline enuresis pattern. Statistical analysis was based on a t test (p ≤ 0.05). A subjective scale was also used to assess patients’ and their parents’ satisfaction. Tolerability and side effects were also documented in the study. Results: Both HCTZ and placebo were statistically effective in reducing the average percentage of wet nights. HCTZ resulted in a significantly better reduction than placebo (41.1 vs. 32.5%; p ≤ 0.023). Overall short-term clinical cure and improvement, on the other hand, were comparable to those of placebo according to the standards of the International Children’s Continence Society. Satisfaction, as a crude measure of success, was expressed more frequently in patients who received HCTZ (20 vs. 9). Both drugs were well-tolerated. Conclusion: The use of HCTZ in the treatment of nocturnal enuresis has never been previously evaluated. The drug, in this pilot study, has a promising statistical superiority to placebo. Its clinical value, however, deserves further definition in future controlled trials.