One of the challenges in the management of primary monosymptomatic enuresis (PME), especially in adolescents, is response failure to medical regimens such as desmopressin. This prospective study aimed at addressing the efficacy of sertraline in the treatment of 25 adolescents (13-18 year old) with PME having experienced failure to previous desmopressin therapy. Patients were recommended to take one oral tablet of sertraline (50 mg) every morning after meal for 3 months. The patients were followedup every 6 weeks, the final visit being 6 months after treatment termination. Comparing the number of wet nights in the pretreatment nocturnal records with the follow-up visits revealed a significant reduction (P=0.01). The primary efficacy outcome was achieved in 18 (72%) of the 25 patients; 12 patients had full response, whereas six patients showed partial response. Four (16%) of the 25 children presented with a relapse after 6 months of follow-up. Drug-related adverse events were rare. Sertraline effectively reduced the number of wet episodes in adolescents with PME who had experienced failure to desmopressin therapy. With respect to the favorable efficacy outcome of this medication and the scarce drug-related adverse effects, sertraline can be proposed as a novel treatment for PME.