OBJECTIVE To evaluate the clinical results of monotherapy with combination therapy in treatment of primary monosymptomatic nocturnal enuresis (PMNE) in children. METHODS Between December 2008 and May 2013, we reviewed the records of 176 children with PMNE. The monotherapy group received 120 micrograms of desmopressin melt whereas the combination therapy group received 120 micrograms of desmopressin melt plus 1-2 mg oral tablet of tolterodine. The degree of response was evaluated at 1-3 months during the treatment and 6 months after complete cessation of treatment protocol. RESULTS Between 176 children, 84 and 92 patients received monotherapy and combination therapy, respectively. There were no statistical differences in gender, age, or baseline monthly frequency of PMNE between the two groups. At baseline, patients had an overall mean of 23.6 ± 5.6 wet nights per month, which decreased to 10.8 ± 5.6 and 7.3 ± 5.3 in monotherapy group and 8.9 ± 9.5 and 3.3 ± 4.9 in combination therapy group at 1 and 3 months after treatment. The rates of Complete plus Partial Response to treatment at 1 and 3 months for monotherapy and combination therapy group were 63.1% and 73.9% vs 72.5% and 93.47% (P value .12 vs .006). The relapse of PMNE 6 months after complete cessation of treatment was 16.39% and 9.09% for monotherapy vs combination therapy group. CONCLUSIONS This study supports the efficacy of combination therapy with desmopressin melt plus oral tolterodine over monotherapy with desmopressin melt in the first-line treatment of PMNE in children.