Serum-mediated impairment of lymphocyte function was studied in an animal model. Sprague-Dawley rats inoculated intraperitoneally or subcutaneously with the Walker 256 carcinoma underwent sequential sampling of blood. The effect of these serum samples upon phytohemagglutinin-induced blastogenesis of normal rat splenocytes was monitored in an assay utilizing incorporation of (3H)-thymidine. The effect of serum samples from both the subcutaneously and the intraperitoneally inoculated tumor-bearing animals was biphasic. Early on, serum enhanced blastogenesis and later suppressed blastogenesis. Separation of sera into high and low molecular weight components by ultrafiltration demonstrated the enhancing activity to reside in the high molecular weight fraction. The enhancing activity of sera decreased over time from tumor inoculation. Conversely, suppressor activity increased over time from tumor inoculation. This study demonstrated that suppressor activity of sera obtained from animals with advanced tumors is the result of the lack of enhancing activity coupled with the elaboration of suppressor activity.