The purpose of these experiments was to evaluate the possibility that the systemic administration of liposomes containing synthetic macrophage activation CGP 31362 or CGP 19835 in mice which were simultaneously receiving injections of gamma-interferon or interleukin 2 would lead to enhanced regression of spontaneous lung metastases produced by syngeneic renal adenocarcinoma. The kidneys of BALB/c mice were given injections of renal adenocarcinoma cells, and 10 days later the kidney with local tumor was surgically resected. These mice were then given injections i.v. with liposomes and with gamma-interferon (s.c.) or interleukin 2 (i.p.). Systemic administration of MLV-CGP 31362 and MLV-CGP 19835A significantly reduced the number of lung metastases in nephrectomized mice. Both lung tumor burden and regional recurrence were further reduced by the s.c. injection of gamma-interferon or i.p. injection of interleukin 2. Long-term survivors were observed only in the groups of animals treated with liposomes containing macrophage activators and with lymphokines. Evaluation of host responsiveness to this immunotherapy revealed in situ activation of alveolar macrophages by administration of MLV-CGP 31362 or MLV-CGP 19835A, which was enhanced in mice also treated with interleukin 2. Normal levels of natural killer cell activity were reduced in the spleens of tumor-bearing mice but were restored subsequent to treatment with MLV-CGP 31362. These results indicate the potential usefulness of treating metastatic renal cell carcinoma by systemic administration of liposomes containing synthetic macrophage activators in combination with parental injections of lymphokines.