This study investigated the toxicological, hematological and immunological effects of diets supplemented with levamisole and ivermectin on Colossoma macropomum. Fish were fed for 24, 96 and 240 h with diets containing 300, 600, 900 and 1200 mg of levamisole kg-1 of feed. None of the levamisole concentrations caused either mortality or behavioral alterations among the fish over 10 d of feeding. In comparison, a single feeding of ivermectin at 4500, 9000, 13500 or 18000 mg kg-1 caused 100% mortality among the fish within 10 h. There were no alterations in erythrocyte parameters or albumin in any treatments with levamisole after 24, 96 and 240 h of feeding. At concentrations of 900 and 1200 mg kg-1, levamisole caused decreases in the albumin-to-globulin ratio compared to the control group and the 300 and 600 mg kg-1 diet treatment groups. Levels of glucose and total plasma protein were higher in the fish fed with 600, 900 and 1200 mg kg-1 than in the controls and the 300 mg kg-1 diet treatment group. After 10 d of receiving feed supplemented with levamisole, globulin levels were higher in the 600 mg kg-1 group than in the controls. Respiratory burst activity of leukocytes also increased in the fish supplemented with the 900 and 1200 mg kg-1 diets compared to the controls and other treatments. This is the first study to investigate how diets supplemented with these drugs affect C. macropomum. Our research indicates that all the levamisole concentrations tested can be used in the diet of C. macropomum for antiparasitic treatments against helminth species, and that dietary treatments with levamisole can stimulate components of the innate immune system.