Objective To evaluate, in a retrospective study, the response rate of older children to combination therapy using a sustained-release anticholinergic agent, hyoscyamine, and a synthetic analogue of antidiuretic hormone, desmopressin acetate. Patients and method Twenty-eight patients (20 males and eight females, aged 9-18 years) diagnosed with nocturnal enuresis were evaluated using a questionnaire, history and physical examination. None had success with single-agent pharmacological therapy. All were begun on 0.375 mg of hyoscyamine and 20 mu g of desmopressin intranasally at bedtime. The response rate was monitored at 2 and 4 weeks, and then every 3 months by recording dry nights on a calendar. To improve efficacy, the dosage of medication was adjusted up to 0.750 mg of hyoscyamine and 60 mu g of desmopressin. Upon achieving dryness and spontaneous awakening to void, medication doses were tapered. Results Within 6 months 16 (57%) patients were completely dry and six (21%) were dry at least 80% of nights. Nine patients relapsed during dose tapering and therapy was reinstituted. Presently, 17 (60%) patients are off medication (after a mean of 8 months of medication). Eight patients are still on medication and are dry at least 80% of nights. Combination therapy failed in three patients and they have transferred to a different regimen. None experienced untoward side-effects from the medications. Conclusion Most older children with nocturnal enuresis responded to combination therapy. These children require long-term follow-up and may need medication for up to 6 months because the relapse rate is fairly high. Combination therapy appears safe and reliable in treating nocturnal enuresis in older children who have had no success with other treatment modalities.