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To investigate the relation between the size of circumoval granulomas and hepatic fibrosis, a variety of mouse strains infected with Schistosoma mansoni were examined and the number of eggs in the tissues, the fibrotic responses to the eggs, and the volume of the granulomas were determined. Marked differences in granuloma volume and in hepatic fibrosis were found between mouse strains, and those strains with the largest granulomas also showed the most hepatic fibrosis. On the other hand no significant correlation between granuloma size and hepatic fibrosis was found in the progeny of the F2 generation and backcrosses between F1 mice and the parental strains when crosses were made between Nmri mice (high granuloma volume and high fibrosis) and C57BL/6 mice (low granuloma volume and low fibrosis). Hepatic fibrosis per egg decreased with increasing infection intensity while granuloma volume was unaffected, indicating that fibrosis and granuloma size are at least in part modulated by different factors. The number of eggs found in the tissues per worm pair and the proportion of eggs in the liver also decreased as infection intensity increased. Some influence of the major histocompatibility complex on both granuloma size and fibrosis was found. Congenic mice on the C57BL/10 and C3H/HeSn backgrounds showed larger granulomas in H-2b than in H-2k mice, but no such correlation was found in comparing C57BL/6 mice with B6.H-2k mice. Less hepatic fibrosis was found in B10.M (H-2f), B10.SM (H-2v), and B10.RIII (H-2r) animals than in C57BL/10 mice. The regulation of granuloma size and of hepatic fibrosis is clearly complex and involves genes both outside of and within the major histocompatibility complex.