Desmopressin is well accepted as first-line medical therapy for enuresis. If ineffective, combination therapy of desmopressin + oxybutynin or desmopressin + imipramine has been used. This study assessed the efficacy of adjunct therapy with either imipramine or oxybutynin in the management of enuresis patients who failed desmopressin treatment.A retrospective chart review of our database for patients with enuresis was performed. Patients who were prescribed desmopressin, oxybutynin, and imipramine over 14 years for enuresis were included. Two cohorts of patients were examined; group OXY was treated with desmopressin and oxybutynin, and group IMP received desmopressin and imipramine. Pretreatment measurement of Vancouver Symptom Scores (VSS) were used to compare groups using the VSS question "I wet my bed at night" where 4: every night, 3: 4-5 nights per week, 2: 1-2 nights per week, 1: 3-4 nights per month, and 0: never. International Children's Continence Society (ICCS) criteria for continence success was utilized to determine outcomes.2521 patients prescribed one of the 3 medications were identified. Among them, 81 patients (mean age: 10.5 ± 2.8 years) received combination therapy. Of which, 55 were male and 26 female. Specifically, 58 were prescribed both desmopressin and imipramine (group IMP), 23 desmopressin and oxybutynin (group OXY), and 4 transitioned from OXY to IMP. Mean pretreatment VSS showed no difference between groups. Both groups experienced minimal drops in wet nights with desmopressin alone. A comparison revealed that group IMP reduced wet nights significantly more than group OXY (VSS wet night score 0.7 ± 1.2 vs. 2.3 ± 1.1 respectively, p < 0.0001). Non-intent-to-treat complete response rate was 68% vs 5% (OR = 42.5, p < 0.001) (IMP vs. OXY respectively). Intent-to-treat response rates were 58%.Although first-line desmopressin treatment for enuresis is effective, it does not work for all patients, and many parents and children desire nighttime dryness. Clinicians have combined desmopressin with oxybutynin or imipramine for improved results, but research comparing these modalities is scarce. Our study suggests that the desmopressin and imipramine combination is superior at reducing nights wet compared to desmopressin and oxybutynin, attributed to imipramine's probable central mechanism rather than its secondary anticholinergic properties. Limitations include a modest sample size, retrospective design, and subjective responses to the Vancouver questionnaire.A combination of desmopressin and imipramine was more effective in reducing wet nights and had a complete response rate that was 42.5 times greater than desmopressin and oxybutynin.