A study was conducted to determine the effect of dietary levels of lipid and vitamin E on growth performance, immune responses and resistance of Nile tilapia to Streptococcus iniae challenge. A basal purified diet (35% protein and 3.4 kcal DE/g) supplemented with 6, 10 and 14% of 1:1 mixture of corn oil and menhaden fish oil was each supplemented with 50, 100 and 200 mg vitamin E/kg. Each diet was fed to Nile tilapia in triplicate aquaria for 12 weeks. Weight gain, feed intake and survival were not affected by dietary levels of either lipid or vitamin E. Feed efficiency in fish fed 14% lipid diets was significantly lower than that fed 6% dietary lipid but these did not differ from that of the 10% dietary lipid diet. These variables were not affected by dietary vitamin E levels. Whole body lipid significantly increased in fish fed 14% lipid diets and 100 mg/kg vitamin E diets. Liver α-tocopherol levels were reflective of dietary levels of vitamin E. Increasing dietary levels of lipid to 14%, however, significantly decreased liver concentration of α-tocopherol. Hematological parameters and hepatosomatic indices were not affected by dietary treatments. Serum protein significantly increased in fish fed 14% lipid diets but was not affected by supplemental levels of vitamin E. Lysozyme activity was not affected by dietary lipid levels but significantly increased in fish fed 200 mg vitamin E diets. Alternative complement activity significantly decreased in fish fed 10 or 14% dietary lipids but increased when dietary vitamin E levels was increased to 100 or 200 mg. Dietary lipid and vitamin E levels had no effect on the resistance of Nile tilapia to S. iniae infection and on antibody titer against that bacterium.