Monotherapeutic strategies often have only partial success in primary nocturnal enuresis (PNE). This analysis evaluated whether adjuvant treatment strategies improve outcomes. PNE children were submitted to a distinct therapeutic strategy including urotherapy (behavioral modifications), a first-line and, if necessary, a second-line treatment period. Outcome was the relief of bedwetting, the follow-up was 3-79 months. Urotherapy was applied. Nonresponders were assigned to desmopressin as first-line treatment. For complete responders a structured withdrawal program was applied. Partial responders were assigned to adjuvant second-line treatment according to their individual symptomatology, masked at basic investigations, incorporating either anticholinergics (propiverine hydrochloride), biofeedback, alpha-blocker (alfuzosin), alarm or psychotherapy, in addition to desmopressin. Nonresponders were referred to specialized management. The study included 259 children suffering from PNE (92 girls, 167 boys, aged 5-18 years): 42 children were relieved from bedwetting after urotherapy and 136 children had a complete response to desmopressin. Three nonresponders were assigned to specialized management, 61 partial responders had adjuvant treatments, and 17 partial responders had no further treatment. The suggested treatment algorithm resulted in 227 complete responders, 29 partial responders, and 3 nonresponders. The need for preliminary urotherapy is evident. The proposed desmopressin monotherapeutic strategy, incorporating a structured withdrawal program, is more effective than the standard desmopressin treatment module. Applying adjuvant treatment modules improves the complete response rate up to 88%. In partial responders overall efficacy rates are improved further. Nonresponders (1.2%) will be referred to specialized management, but many partial responders will gain improvement sufficient to refrain from invasive procedures.