In the absence of interleukin-4 (IL-4), infection with Schistosoma mansoni leads to a severe fatal disease rather than the chronic survivable condition that occurs in wild-type (WT) mice. Because the sustained production of NO most closely correlates to weight loss and fatality in infected IL-4^/ mice and because gamma interferon (IFN-) is an important inducer of inducible NO synthase, infected IL-4^/ mice were treated with anti-IFN- antibodies to determine the role of IFN- during schistosomiasis in WT and IL-4^/ animals. When IFN- was neutralized, Th2 responses were enhanced and NO production was reduced in both WT and IL-4^/ mice. The decreased NO production correlated with a rescue of proliferation in splenocytes from infected IL-4^/ mice. Furthermore, the neutralization of IFN- in vivo improved the gross appearance of the liver and led to a reduction in granuloma size in infected IL-4^/ but not WT mice. However, the neutralization of IFN- in vivo did not affect the development of severe disease in infected IL-4^/ mice. These results suggest that while the increased production of IFN- does lead to some of the pathology observed in infected IL-4^/ mice, it is not ultimately responsible for cachexia and death.