High-dose chemotherapy frequently causes injury to the gastrointestinal mucosa, resulting in diarrhea. The purpose of the current study was to assess the tolerability and efficacy of enterade ® in reducing ≥ grade 2 diarrhea (G2D) in association with high-dose melphalan followed by autologous stem cell transplantation (ASCT). We conducted a prospective, double blinded, multi-center trial in which 114 subjects were randomized to receive enterade ® or placebo twice daily during the transplant hospitalization. Gastrointestinal toxicities (nausea, vomiting, oral mucositis and dysphagia) resulted in poor study compliance in both arms. Among subjects who were able to complete planned therapy (13%), the incidence of G2D was lower for those receiving enterade ® as compared to placebo (16% vs 86%, p<0.03). Twice daily oral administration of enterade ® and placebo following high-dose chemotherapy and ASCT was not feasible due to significant gastrointestinal toxicities. Future explorations of enterade ® should be conducted in populations capable of reasonable oral intake.