The toxicity of gossypol, a compound occurring naturally in the cotton plant, was investigated in Trypanosoma brucei-infected, gossypol-treated rats, with and without protein malnutrition. The liver, heart, lungs, spleen and adrenal glands were enlarged in all gossypol-treated rats. Gossypol treatment or trypanosome infection, either alone or together, invariably caused significant reductions in the serum activity of creatine phosphokinase and amylase and in the serum concentration of cortisol. The serum biochemical changes, together with histopathological findings in various organs, indicated that the toxicity of gossypol and pathology of trypanosome infection, either alone or in concert, could be exacerbated by protein malnutrition. This finding suggests that the previously reported antiparasitic properties of gossypol may be of little ultimate benefit due to these serious side effects. The spleen in the protein-malnourished, trypanosome-infected and gossypol-treated animals exhibited only a slight decrease in the number of lymphatic nodules, but a marked cellular depletion, especially of cortical tissue, was observed in the thymus. These observations would seem to justify further study of the immune status of trypanosome-infected, gossypol-treated animals.