Gossypol, a pigment of cotton, is a hepatic toxin for chickens. Thus, despite its high protein content, inclusion of cottonseed meal in poultry diets is problematic. Silymarin, an extract from milk thistle, has hepatoprotective qualities and could potentially serve as a feed additive to offset the toxicity of gossypol. The objective of this study was to determine if silymarin could counteract gossypol toxicosis. Cockerels (n = 144) from lines divergently selected for humoral immunity were used. Three individuals from each line were randomly assigned to a cage and fed a corn-soybean meal (control) diet for 14 d. Six cages per line were then randomly assigned 1 of 4 dietary treatments (1,000 mg/kg of gossypol, 1,000 mg/kg of silymarin, 1,000 mg/kg of both gossypol and silymarin, or a control diet). Body weight and feed intake data were collected for 21 d, with chickens bled weekly to collect plasma and determine hematocrits. Chickens were then killed, and livers were collected for subsequent histology and enzymatic activity analyses. Endpoints measured weekly were analyzed with repeated measures and regression methodologies. Plasma and liver enzyme activities, and histological measures, were analyzed using ANOVA. No significant interactions between diets and lines were observed. Chickens assigned to the gossypol and gossypol-silymarin diets stopped gaining weight at d 14 (P < 0.001) and lost weight by d 21 (P < 0.001). Gamma glutamyltransferase was also elevated in these chickens at d 14; activities increased further by d 21 (P < 0.001). Histological examination of liver slices indicated substantial lipidosis (P < 0.001). Furthermore, quinone reductase activity was higher in gossypol- and gossypol-silymarin-treated chickens than in control and silymarin-treated chickens (P < 0.001). Silymarin did not alleviate any clinical effects of gossypol toxicosis.