Five sheep were exposed to 5,000 S. mansoni cercariae percutaneously and the stools examined for 20 wk to determine patency. The sheep were found to be partially susceptible to a primary infection and showed great individual variations in their pathophysiological responses. All of the sheep acquired a patent infection with S. mansoni and eggs were first seen in feces 9 wk postexposure with no eggs detected after 14 wk. At necropsy 20 wk postexposure only dead S. mansoni worms were found. KOH digests revealed that tissue egg counts were low, ranging from 0 to 133 in the liver, and 0 to 257 in the intestine. Primary infection of sheep with S. mansoni followed by oral infection with F. hepatica metacercariae 10 wk later resulted in a reduction of 51% in F. hepatica worms recovered over controls infected with F. hepatica for 10 wk. All 5 of the S. mansoni-infected/F. hepatica-challenged sheep developed 71 or less F. hepatica worms. In contrast, 3 of the 5 F. hepatica-infected sheep developed 113-197 worms. However, although the experimental mean worm burden was lower than the control group, the variability in the control group was too great to obtain significance between the groups. There was a clear tendency toward normocytic normochromic anemia following a primary infection with S. mansoni; however, blood values were more reduced in the F. hepatica challenge controls than in the animals that received primary infection with S. mansoni.