The ability of host plants to influence permeability of the peritrophic matrix (PM) in insects has received very little attention. For several years, we have been studying mechanisms whereby Heliothis virescens larvae fed cotton foliage shortly before challenge with Autographa californica nucleopolyhedrovirus (AcNPV) experience decreased viral mortality compared with larvae fed artificial diet. We hypothesize that one mechanism responsible for this difference is diminished permeability of the PM to virions, reducing the establishment of primary midgut infections in cotton-fed insects. To test this hypothesis, we fed fourth instar H. virescens with granules of Trichoplusia ni granulovirus (TnGV) prior to challenge with AcNPV. TnGV granules contain enhancin, a metalloprotease known to disrupt the PM in several lepidopteran species. Enhancin increased mortality by AcNPV in cotton-fed larvae to the same level as mortality in diet-fed larvae. Although exposure to enhancin also increased mortality in diet-fed insects, it was not statistically significant, suggesting that the PM is not a substantial barrier to AcNPV infection in diet-fed H. virescens. As expected, Western blots prepared from PM surrounding frass collected from these larvae showed that enhancin had degraded invertebrate intestinal mucin in the PM, indicating that the PM had been disrupted. Detailed pathogenesis studies designed to document the impact of enhancin on the timing and number of midgut and tracheal infections are underway. To date, our results support the hypothesis that inhibition of baculoviral disease in cotton-fed insects involves reduced permeability of the PM to occlusion-derived virus.