PSC 833 is an effective MDR1 reversal agent in vitro, including studies with paediatric cancer cell lines such as neuroblastoma and rhabdomyosarcoma. This study was performed to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in children with solid tumours and to determine the influence of PSC 833 on the pharmacokinetics of co-administered etoposide. Each patient received one cycle of intravenous etoposide (100 mg/m2 daily for 3 days on three consecutive weeks) to document baseline pharmacokinetics, and subsequently the same schedule using a dose of 50 mg/m2 was given combined with PSC 833 given orally every 6h at a starting dose of 4 mg/kg. Thirty two eligible patients (23 male, median age 8.3 years) were enrolled. Neuroblastoma and rhabdomyosarcoma were the common disease types. Brain tumours were excluded. DLT was defined as any non-haematological grade 3-4 toxicity (common toxicity criteria) and using a specific toxicity scale for cerebellar toxicity. The MDT was defined as the first dose below which 2 or more patients per dose level experienced DLT. Grade 1-2 ataxia occurred in cohorts 2 and 3 (4 and 5 mg/kg, respectively). Three patients developed grade 3 neurotoxicity in the 6 mg/kg cohort and this defined the MTD. Six responses were observed (2 CR, 4 PR). Pharmacokinetic studies indicated that the clearance of etoposide was reduced by approximately 50% when combined with PSC 833. It is concluded that the toxicity profile and MDT is similar in both children and adults, as is the effect on etoposide metabolism. The study demonstrated the feasibility and safety of carrying out a paediatric phase 1 trial across European boundaries and acts as a model for future cooperative studies in rare cancers among children.