To further understand the effects of opiates on the pathogenesis of infectious disease, naturally occurring pathogens were studied in a swine model. Swine were given morphine for 21-42 days to establish a tolerant, dependent state. On day 7 after morphine initiation, pigs were challenged with swine herpesvirus-1 (SHV-1); on day 14, selected animals were superinfected with Pasteurella multocida. Evaluations were made ofthe clinical disease, protective effect ofSHY-1 vaccination, and pathology. Morphine-dependent animals developed significantly greater virus-induced and secondary bacterial pneumonia. Prior vaccination with SHY-1 was not protective against pneumonia in morphine-dependent pigs. Unexpectedly, clinical signs associated with neurologic disease were less pronounced, and mortality from viral encephalitis was decreased in morphinetreated animals. Collectively, the findings demonstrate that morphine dependence is associated with a marked alteration of the pathogenesis of SHY-1 and that the effects of this opiate on pathogenesis are determined by the specific site of infection.