Many paediatric oncology centres apply parenteral nutrition (PN) in children with severe oral mucositis after chemotherapy. However, no convincing data exist to support this treatment strategy. The aim of our study was to elucidate a possible advantage of PN versus intravenous replacement fluid therapy (FT). In a prospective randomized study, 30 children with mucositis WHO grade IV were assigned to receive either PN or intravenous replacement FT. Weight, total body water, fat-free mass (measured by impedance analysis) and peripheral white blood cells were assessed daily. For aspects of quality of life and economics, the length of hospital stay, the incidence of infections, the days on intravenous antibiotics and delay of scheduled chemotherapy were examined. Children with PN gained body weight significantly compared to baseline and to FT due to an augmentation of fat mass while total body water and fat-free mass significantly decreased. In children with FT, body weight remained stable while total body water and fat-free mass significantly increased, thereby loosing fat mass. We observed no differences in recovery of peripheral white blood cells (WBC), incidence of infections, hospitalization time, days on intravenous antibiotics, days on opioid analgesics and delay of the next scheduled chemotherapy cycle. Although children with PN gained weight in form of fat mass, this did not translate into a clinical benefit for the patients such as earlier recovery of WBC counts, shorter hospitalization time, a decreased use of analgesics or less delay of the next scheduled chemotherapy cycle. Our findings therefore do not support the hypothesis that PN is superior to FT when used for less than 10 days for oral mucositis.