Abstract Objective To investigate why not all children with monosymptomatic nocturnal enuresis (MNE) treated with desmopressin give an adequate response. Materials and methods We included 114 children with MNE aged 5–15 years (9.8 ± 0.2 years) who experienced at least 1 wet night and more than 2 dry nights during desmopressin treatment. The patients made home recordings for 2 weeks as baseline and for 2–4 weeks of desmopressin titration. Nocturnal urine production during wet and dry nights, and maximum voided volumes (MVVs) were documented in all patients. Results Sixty-four patients were desmopressin non-responders, 29 were either partial responders or responders, while 21 patients were full responders. Desmopressin reduced nocturnal urine production dramatically during dry nights compared with pre-treatment wet nights. Nocturnal urine production during desmopressin treatment was significantly greater during wet nights compared to dry nights (243 ± 9.32 vs 176 ± 5.31 ml, P < 0.001). There was a highly significant correlation between individual nocturnal urine output and MVV, and dry nights were characterized by nocturnal urine output/MVV ratios well below 1.0. Conclusion The anti-enuretic response to desmopressin seems to be dependent upon the degree of reduction in nocturnal urine production. Research on desmopressin bioavailability in children is needed.