Lymphokine-activated killer (LAK) cells were induced by incubating strain 2 guinea pig splenocytes or lymph node-derived cells in recombinant human interleukin-2 (IL-2) for 3-5 days. These effector cells had the morphology of lymphoblasts and were able to lyse murine P815 tumor cell targets. Fresh, unstimulated, guinea pig effectors were not capable of lysing these targets. The therapy of the L2C leukemia, an acute B-lymphoblastic leukemia of strain 2 guinea pigs, using LAK cells and recombinant IL-2 was examined. Antitumor effects were demonstrated by premixing LAK and tumor cells prior to intradermal injection in Winn type assays and then measuring the growth of local tumor and survival of the animals. In further experiments i.p. administration of LAK cells, 4 h following tumor cell inoculation by the i.p. route, prolonged the survival of treated animals. The best results in this i.p. therapy model were obtained with a 10-fold excess of LAK cells over tumor cells plus additional treatment with 1000 units of IL-2 for 20 days. This resulted in a 10-day increase in median survival of treated animals. Despite these in vivo antitumor effects, lytic activity of LAK effector populations against L2C targets could not be demonstrated in vitro. The potential synergy between LAK cells, IL-2, and a monoclonal antibody directed against the idiotype of the neoplastic cell surface immunoglobulin was also investigated. In these experiments enhanced survival of the combined treatment group, beyond that of either singly treated group, was not found. This study shows that LAK cells are useful agents in the therapy of a widely disseminated, aggressive, B-cell lymphoblastic leukemia. The use of such effectors, even in cases where in vitro lysis of the target tumor cell cannot be demonstrated, is encouraged by these results.