We have previously reported on the antimetastatic effects of experimental adoptive immunotherapy using plastic adherent lymphokine-activated killer cells (ALAK) cells (R. E. Schwarz et al. Cancer Res. 49: 1441, 1989). We have also reported that the spleen is a superior source of lymphocytes for A-LAK cell generation (R. E. Schwarz and J. C. Hiserodt, Med. Hypotheses 28: 165, 1989). This study, therefore, was designed to examine the effects of splenectomy itself on tumor growth in an experimental animal model. Natural killer (NK)-resistant MADB106 mammary adenocarcinoma cells were injected iv into F344 rats to generate multiple lung metastases. Splenectomies (Sx) were performed on Days −6, −3, −1, 0, 1, 3, 6, and 10, counted from the time of tumor injection. Groups consisted of six animals each, and shamanesthetized and -operated animals served as controls. Splenectomies, if performed between Days −3 and +1, had significant antitumor effects as documented by the number of outgrowing surface metastases (5 ± 7 vs >300; P < 0.0001) and by animal survival (>100 vs 21 ± 3 days; P < 0.001). However, splenectomies, performed at an earlier or later stage, did not show these effects. Sx did not alter peripheral blood NK activity or the percentages of mononuclear cell subsets except for a slight decrease in the T-helper/T-suppressor ratio (P < 0.04). Interleukin 2 (rhIL2), given at 2.5 × 10⁵ U/kg/day for 3 days immediately after splenectomy, completely abrogated the observed antitumor effects. Subcutaneous tumor rechallenge of long-term surviving animals showed no tumor take in 87% of the animals. We conclude that the development of tumor-specific immunity in this model is facilitated, if splenectomy is performed during a critical interval, and is abrogated by IL2 administration. Splenectomy can show significant immunomodulatory and/or therapeutic effects in tumor-bearing individuals.