Vesicular stomatitis virus (VSV) matrix (M) protein blocks host mRNA export from the nucleus and thereby inhibits interferon induction in infected cells. M mutants with mutations of methionine 51 (M51) lack this shutoff function. We examined pathogenesis of a VSV M mutant with a deletion of M51 (VSVDeltaM51) after intranasal infection of BALB/c mice and found an unexpected phenotype. Mice that received VSVDeltaM51 experienced a more rapid but overall less severe weight loss than mice that received the recombinant wild-type VSV (rwtVSV). Rapid weight loss was not explained by faster initial replication because VSVDeltaM51 replication was controlled faster than rwtVSV replication in the lungs and did not spread systemically like rwtVSV. This faster control of VSVDeltaM51 correlated with a more rapid induction of interferon in the lung. Because tumor necrosis factor alpha (TNF-alpha) is associated with weight loss, we examined TNF-alpha induction in mice infected with rwtVSV or VSVDeltaM51. We found more-rapid induction of TNF-alpha by the mutant at early times after infection, while rwtVSV induced more TNF-alpha later in infection. This result suggested that TNF-alpha induction might explain both the rapid weight loss caused by the mutant and the overall greater weight loss caused by the rwtVSV. Using TNF-alpha knockout mice (C57BL/6 background), we showed that weight loss following rwtVSV infection was greatly reduced in the absence of TNF-alpha. Although the rapid weight loss caused by VSVDeltaM51 was less pronounced in C57BL/6 mice, it was eliminated in the absence of TNF-alpha. These results indicate a role for TNF-alpha in the pathogenesis of VSV.