Abstract Background: Nocturnal enuresis is a symptom with probably multiple etiologic factors and a high prevalence. Conventional therapies is expensive and complicated, since the effect of calcium on voiding dysfunction was approved. Therefore, to the current study aimed at evaluating the therapeutic effect of hydrochlorothiazide on primary monosymptomatic nocturnal enuresis (PMNE). Methods: The current study was conducted based on the interviews with patients. Morning urine test was evaluated in children with PMNE detection and specific gravity < 1010 enrolled to the study (110 children comprised of 57 cases and 53 controls). Children were divided into 2 groups; in the case group, hydrochlorothiazide (tablet 1 mg/kg and maximum 50 mg) was administered in the morning and the control group was only given necessary training about enuresis. For 3 times and with 1 month interval (based on a predetermined questionnaire) the frequency of nocturnal enuresis was checked. Data were transferred into SPSS program and the therapeutic effect of hydrochlorothiazide on primary monosymptomatic nocturnal enuresis was investigated. Findings: There was a statistically significant difference regarding the frequency of nocturnal enuresis between the 2 groups (P = 0.0001). Also, both groups were matched by age (P = 899) and gender (P = 607). Conclusions: Hydrochlorothiazide can be used as an effective and safe therapeutic option for treatment of primary monosymptomatic nocturnal enuresis.