Protein‐calorie malnutrition (PCM) is prevalent in cancer patients. However, the effect of PCM on antitumor immunity is unclear and critically important in an era of improving results with adoptive immunotherapy. This study examined the effect of short‐ and long‐term PCM on tumor‐specific and natural immune effector mechanisms in a murine neuroblastoma (C1300 NRB) model. A/J mice received an isocaloric 2.5% or 24% casein diet for 3 or 8 weeks before innoculation with tumor. Three weeks later lymphocytes from tumor‐bearing mice were harvested for determination of cytotoxic T lymphocyte (CTL) generation and natural killer (NK) cell cytotoxicity. Both 3 and 8 weeks of PCM significantly reduced mean total body weight by 25% (p<0.001) and 41% (p<0.001), respectively, compared with regularly nourished mice. Short‐term PCM did not inhibit CTL or NK cytotoxicity, whereas long‐term PCM significantly diminished CTL generation (p<0.001) but preserved NK cytotoxic function. These results indicate that CTL development against autologous tumor, in contrast to basal NK function, is dependent on host nutritional status. Mean tumor growth, determined by tumor‐weight to carcass‐weight ratio, was unchanged for both short‐and long‐term protein‐energy deprived groups compared with results in regularly nourished mice. These findings suggest that NK function is the predominant effector mechanism inhibiting C1300 NRB growth and that NK tumorcidal capacity is preserved during PCM.(Journal of Parenteral and Enteral Nutrition15:15–21, 1991)