The toxic effects of methotrexate administration [20 mg/kg, bolus intraperitoneally (ip)] to rats fed a regular chow diet (n = 10) was compared with results in animals fed an elemental, chemically defined, liquid diet (n = 10) for 7 days. All animals receiving an elemental diet became anorectic and lethargic within 60 hr of methotrexate injection. All animals in this group subsequently developed enteritis and died within 150 hr. There was no clinical evidence of enteritis in rats fed a regular chow diet and mortality as zero in this group (p less than 0.001). In a second study one group of rats (n = 9) was fed a regular chow diet for 7 days; four groups were fed an elemental, chemically defined, liquid diet (n = 9 per group) for 7 days. At 24 hr and 8 hr prior to, or 24 hr after methotrexate administration, one group was refed a regular chow diet; the fourth group was maintained on an elemental liquid diet throughout the study period. All rats fed a regular chow diet survived following methotrexate injection (20 mg/kg, ip). All rats fed an elemental diet throughout the study period died. Those rats refed a regular diet 24 or 8 hr prior to methotrexate injection demonstrated a significant improvement in survival (100% in the 24-hr group, 55% in the 8-hr group). However, those animals refed a regular diet 24 hr after methotrexate injection demonstrated a 100% mortality.(ABSTRACT TRUNCATED AT 250 WORDS)