Children with attention deficit hyperactivity disorder disproportionately experience voiding dysfunction and persistent nocturnal enuresis due to a combination of sphincter and detrusor overactivity and nocturnal polyuria. The different treatment approaches to nocturnal enuresis often fail in these patients. Therefore, we performed a prospective study to compare the efficacy of combination therapy with desmopressin and oxybutynin vs the tricyclic antidepressant imipramine in patients with attention deficit hyperactivity disorder who have nocturnal enuresis. A total of 54 patients with attention deficit hyperactivity disorder and nocturnal enuresis were randomly stratified into 2 groups. Demographic data on patient age and gender were identical in the 2 groups. Functional bladder symptoms were judged using the dysfunctional voiding symptoms survey. The initial dysfunctional voiding symptoms survey score was similar in the 2 groups. The total survey score was compared between the 2 groups in aggregate as well as specifically regarding the incidence of nocturnal enuresis following treatment. The first group consisted of 27 patients who received desmopressin and oxybutynin, and the second group of 27 was treated with imipramine. Of the 27 children in each group 23 (85%) received methylphenidate for attention deficit hyperactivity disorder. The mean +/- SD initial dysfunctional voiding symptoms survey score in groups 1 and 2 was 20.5 +/- 3.3 and 20.9 +/- 4.1, respectively. Following treatment the mean survey score decreased significantly in groups 1 and 2 (6.5 +/- 2.5 and 9.4 +/- 2.1, respectively, p <0.001). However, between groups analysis showed that the dysfunctional voiding symptoms survey score was significantly lower in group 1 than in group 2 (mean 6.5 +/- 0.5 vs 9.6 +/- 0.4, p <0.001). There was also a statistically significant decrease in the incidence of nocturnal enuresis in group 1 (survey question 2 score 0.9 +/- 0.2 vs 2.9 +/- 0.2). Our data show that there is a high incidence of voiding dysfunction in children with attention deficit hyperactivity disorder. Combination therapy with desmopressin and oxybutynin is a feasible, safe and effective treatment for nocturnal enuresis in these children.