Two immunomodulatory protocols were evaluated for their ability to inhibit lung colonization by mouse mammary tumor line 4T07. Preimmunization with tumor cells or pretreatment with poly I:C were equally effective at inhibiting lung colonization but a clonogenic tumor cell assay demonstrated that the treatments reduced tumor cell burden at different steps during the metastatic process. Poly I:C pretreatment accelerated tumor cell clearance based on the recovery of clonogenic tumor cells from lungs dispersed within 6 h post-arrest. Preimmunization inhibited the subsequent replication of tumor cells which survived and established in the lung, as indicated by the expansion of clonogenic cell numbers between 1 day and 7 days post-arrest. Histologic examination of serial sections of lungs demonstrated that very few (6%) of the tumor cells were extravascular 6 h post-tumor cell injection. By 24 h and 168 h the percentages of tumor cells which were extravascular had increased to 62% and 86%, respectively. Thus, poly I:C pretreatment appears to enhance killing of tumor cells prior to extravasation, whereas preimmunization appears to inhibit tumor cells after extravasation.