The ability of soy protein isolate to reduce the severity of 13-cis retinoic acid (13cRA)-induced hypertriglyceridemia was assessed in an animal model of this condition (rats fed a 13cRA-containing, casein-based diet). Male Fischer 344 rats (N = 7/group) were fed purified diets containing either casein or soy protein isolate and having either no 13cRA or retinoid at a level of 100 mg/kg diet-designated as Groups C, S, C + R, and S + R, respectively. Diet had no effect on either food intake or final body weight, and the serum levels of 13cRA were not significantly different for Groups C + R and S + R. Groups fed diets having 13cRA had significantly (p < 0.05) higher serum triglyceride levels than ones fed the corresponding retinoid-free diets, but the serum triglyceride level for Group S + R was significantly lower than for Group C + R, being 2.99 vs. 6.97 mM (265 vs. 617 mg/dl). Thus, soy protein isolate can reduce the severity of 13cRA-induced hypertriglyceridemia without affecting serum retinoid level.