A new reproductive and respiratory syndrome was recognized in the United States swine population in 1986. Tissue filtrates from affected pigs submitted to the Iowa State University Veterinary Diagnostic Laboratory were used to experimentally inoculate gnotobiotic pigs and reproduce respiratory disease and lesions similar to what was observed on the farms of origin. Cytopathic effects and virus particles consistent with porcine reproductive and respiratory syndrome virus (PRRSV) were observed in cell culture. Virus isolation and serology techniques were standardized. Sixteen U.S. PRRSV isolates from herds with varying disease severity and the European Lelystad virus were plaque-purified. A cesarean-derived-colostrum-deprived pig model was developed to study and compare the pathogenicity of a selected subset of these isolates. Significant differences were detected in severity of clinical disease and gross and microscopic lung lesions. Isolates were grouped into low and high virulence categories. An immunohistochemistry technique for detection of PRRSV antigen in formalin-fixed tissues was developed and standardized for diagnostic and research purposes. PRRSV antigen was detected in alveolar macrophages, macrophages throughout the lymphoid system, dendritic-like cells in tonsil, thymus, spleen and lymph nodes, endothelial cells in the heart, and Kupffer cells in the liver. Temporal analysis of the distribution of virus by isolation, and antigen by immunohistochemistry, suggests that oronasal inoculation results in infection of the tonsil and viremia in 12 to 24 hours with subsequent widespread distribution throughout the respiratory and lymphoid systems. PRRSV was found to persist in tonsils and lung for more than 28 days. Pneumonia likely results from the lysis of alveolar macrophages, altered alveolar macrophage function, and the inflammatory response to the enzymes and cytokines released by PRRSV-induced damage to alveolar macrophages. The prolonged viremia, the persistent infections, and the ineffective immune response may be the result of widespread damage to antigen presenting cells within which PRRSV antigen was consistently demonstrated by immunohistochemistry.