AbstractType of diet influences toxic effects of the chemotherapeutic drug methotrexate (MTX) on the gastrointestinal tract (GI) tract. In this study, commercial enterai products containing various protein types were tested to determine whether they exacerbated or alleviated MTX‐induced GI toxicity in a non‐tumor‐bearing animal model receiving a single injection of MTX (20 mg/kg). Five enterai products containing casein or soy isolate in various forms as the primary source of protein were used. One casein‐based product also contained soy fiber. These diets were compared with a soy concentrate‐based diet and a casein‐based diet prepared by the authors. Each diet was fed to 10 rats for seven days before injection and seven days after injection. In animals fed soy isolate or hydrolyzed or intact casein without added soy fiber, food intake was<30% of pre‐MTX injection levels on Days 3 and 4 after injection. These animals also lost weight and had diarrhea. Rats consuming the casein‐based diet with fiber experienced some protection against MTX toxicity. Food intake only dropped to 63% of preinjection levels, weight was maintained, and no diarrhea occurred. Rats fed soy concentrate maintained food intake above 90% of preinjection levels, which was greater than all other groups at Day 3 and those receiving hydrolyzed or intact casein without fiber on Day 4 (p<0.05). Weight gain in the soy concentrate group was also different from that in groups fed hydrolyzed or intact casein without fiber (p<0.05). Rats consuming soy concentrate had no diarrhea. A second experiment was conducted to evaluate histological damage to the intestine when these diets were fed to animals injected with MTX. This experiment was conducted in the same manner as the first experiment, except animals were sacrificed on Day 3 after injection and samples were obtained from the jejunum. Crypt necrosis occurred in all groups except those consuming the soy concentrate diet or the enterai product containing soy fiber. Results indicate that soy concentrate is superior in alleviating MTX toxicity compared with commercial enterai products.