The administration of chemotherapy is limited in clinical situations by lack of selective antineoplastic activity resulting in significant host toxicity. Although it has been suggested that nutrition support can reduce chemotherapy-related toxicity, few controlled studies exist to document this clinical impression. This study was performed to determine the effect of enteral protein intake on 5-fluorouracil toxicity in tumor-bearing animals. Seventy-nine female Lewis/Wistar rats with subcutaneous mammary tumor implants (AC-33) were randomized to receive either standard protein (22.0% protein; 4.27 kcal/g) or an isocaloric, protein-depleted diet (0.03% protein; 4.20 kcal/g). One-half of the animals in each group received daily injections of 5-fluorouracil (15- or 25 mg/kg ip) or placebo (saline) for 4 or 5 days. Standard protein intake significantly increased host body weight and decreased leukopenia at low (15 mg/kg) and high (25 mg/kg) 5-fluorouracil therapy. At high-dose 5-Fluorouracil (25 mg/kg), the incidence and duration of diarrhea were decreased in animals receiving standard protein intake. Thus, enteral protein intake significantly reduced clinical and objective 5-fluorouracil toxicity and improved body weight in this tumor-bearing animal model.