The most suitable tissue samples and test procedures for the etiologic diagnosis of porcine reproductive and respiratory syndrome (PRRS) were found to depend on several variables including the age of the pig from which tissues were collected, the stage of infection (acute or persistent), the available complement of diagnostic reagents, and the urgency in obtaining results. When the diagnosis involved acute infection of congenitally or neonatally infected pigs, and susceptible cell culture(s) was available for virus isolation, then both serum and alveolar macrophages (AM) were reliable samples. Alveolar macrophages flushed from infected lungs provided a temporal advantage, however, in that in addition to their use for virus isolation, i.e., from a lysate of AM, they could be cultured in vitro and examined for the presence of viral antigens by immunofluorescence microscopy (FA) as early as 1 hour after they were added to the culture vessel. The examination of AM in this manner also circumvented the need for additional cell cultures to test for infectious virus. Testing presuckling sera by indirect FA for antibodies to PRRS virus also was of diagnostic value and, like FA with AM, could be completed soon after sample collection. For older pigs, AM were more reliable than serum, lungs, or any of 27 other tissues evaluated as diagnostic samples and were often the only samples in which infectious virus and viral antigens were detected when pigs were euthanized more than 3 weeks postexposure. A simple procedure for on-farm collection of AM as well as methods for testing AM for viral antigens and neonatal (presuckling) sera for homologous antibody in a modestly equipped laboratory, such as one that might be maintained by a veterinary practitioner, are described and discussed.