To determine effects of the sera on cell proliferation, schistosomula of Schistosoma mansoni (20-days-old) were incubated in medium containing fetal calf serum plus hamster (highly susceptible host) portal or peripheral venous serum, or rat (poorly susceptible host) portal or peripheral venous serum in the presence of bromodeoxyuridine (BrdU). Compared with schistosomula cultured in presence of control medium containing fetal calf serum alone, BrdU labeling indices (BLIs) were increased by 39% in the presence of portal, but not in peripheral, serum of hamsters. In contrast, no significant differences were observed in the BLIs in rat portal, or peripheral, sera or in control media. In vivo BrdU labeling results revealed that there was no detectable cell proliferation in S. mansoni schistosomula (6 days old) in the lungs. However, cell proliferation was detected in schistosomula beginning at 17 days. The results indicated that portal venous serum from a highly susceptible host, but not from a poorly susceptible host, stimulated schistosome cell proliferation in vitro. The timing of the increase in cell proliferation in terms of development corresponded to liver portal-mesenteric localization of schistosomula. Together, the data support the conclusion that in susceptible hosts, portal serum may play a role in schistosome cell proliferation, possibly resulting in termination of schistosome migration. This may explain the colocalization of adults, and the known organ selectivity of disease.