Although the immune system is important in antitumor defense, little is know about the immune response during progressive tumor growth. Sprague-Dawley rats (171 +/- 3g) of the Buffalo strain were implanted with the Morris Hepatoma 7777 ([MH 7777] a poorly differentiated, rapidly growing tumor) and killed either 2 (T2) or 3 (T3) weeks postimplantation when the tumor weighed 3.0 +/- 0.4 and 14 +/- 1 g, respectively. Splenocytes were isolated and their phenotypes, metabolism (metabolite production from glucose and glutamine), proliferative response ([3H]thymidine incorporation in response to polyclonal mitogens), and natural killer (NK) cytotoxicity (lysis of YAC-1 cells) were determined. Five rats were killed with the T2 group to serve as non-tumor-bearing controls (T0). Food intake and nontumor body weight decreased (P < .01) 14 days after tumor implantation. There was a progressive decrease (T3 < T2 < T0) in splenic mitogen responses (P < .05) and plasma essential and nonessential amino acid concentrations (P < .05). Compared with T0, NK cytotoxic activity was significantly (P < .05) lower at T2 and higher at T3. The presence of the tumor at both T2 and T3 resulted in lower production of metabolites from glucose and glutamine by splenocytes. The proportion of CD8+ cells was lower (P < .05) and the proportion of B cells and macrophages higher (P < .05) in spleens from tumor-bearing rats. In conclusion, the presence of even a small tumor burden (1.4% of body weight) significantly altered the host's immune function and metabolism. A larger tumor burden (6% of body weight) increased NK cytotoxic activity and further reduced cell-mediated immune function.