Patients with idiopathic pulmonary fibrosis (IPF) often do worse following infection, but the cause of the decline is not fully understood. We previously demonstrated that infection with a murine gamma herpes virus (γHV-68) could exacerbate established lung fibrosis following administration of fluorescein isothiocyanate (McMillan et al. Am J Respir Crit Care Med 177: 771–780, 2008). In the present study, we anesthetized mice and injected saline or bleomycin intratracheally on day 0. On day 14, mice were anesthetized again and infected with either a Gram-negative bacteria (Pseudomonas aeruginosa), or with H1N1 or γHV-68 viruses. Measurements were then made on days 15, 21, or 35. We demonstrate that infection with P. aeruginosa does not exacerbate extracellular matrix deposition post-bleomycin. Furthermore, fibrotic mice are effectively able to clear P. aeruginosa infection. In contrast, bleomycin-treated mice develop worse lung fibrosis when infected with γHV-68, but not when infected with H1N1. The differential ability of γHV-68 to cause increased collagen deposition could not be explained by differences in inflammatory cell recruitment or whole lung chemokine and cytokine responses. Alveolar epithelial cells from γHV-68-infected mice displayed increased expression of TGFβ receptor 1, increased SMAD3 phosphorylation, and evidence of apoptosis measured by cleaved poly-ADP ribose polymerase (PARP). The ability of γHV-68 to augment fibrosis required the ability of the virus to reactivate from latency. This property appears unique to γHV-68, as the β-herpes virus, cytomegalovirus, did not have the same effect.