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Serum amyloid A (SAA) is an acute phase protein that is expressed rapidly in response to infection and inflammation in vertebrates. Here, we detected the expression of porcine SAA3, an isoform of porcine SAA, during porcine respiratory and reproductive syndrome virus (PRRSV) infection, which is a major threat to the pig industry. In response to PRRSV infection, porcine SAA3 expression was upregulated significantly in porcine pulmonary alveolar macrophages and in extrahepatic tissues, including the lungs and inguinal, mandibular, and hilar lymph nodes, which were affected mainly by PRRSV infection, demonstrating that porcine SAA3 is a tissue-derived isoform that is induced in extrahepatic tissues during the acute phase response. Overexpression of porcine SAA3 increased PRRSV titers in cultured cells, and the exogenous administration of porcine SAA3 facilitated PRRSV adsorption to cells, suggesting that porcine SAA3 assists PRRSV replication. Our data provide insights into the role of porcine SAA3 during PRRSV infection.PRRSV induces porcine SAA3 expression in extrahepatic tissues.Porcine SAA3 is a tissue-derived isoform.Porcine SAA3 assists PRRSV replication.