Influenza A viruses are an important cause of respiratory disease in swine worldwide. Contemporary influenza viruses endemic in North American swine are triple reassortants with multiple subtypes displaying marked genetic and antigenic diversity. Inactivated influenza vaccines are used in swine to protect against infection and clinical disease; however, they often lack the ability to cross-protect against heterologous viruses. In addition, inactivated vaccines may enhance clinical signs and pneumonia following challenge with divergent emerging viruses that do not demonstrate serological cross-neutralizing activity. Herein we describe enhanced disease in pigs administered an inactivated H1N2 delta-cluster vaccine followed by challenge with pandemic A/H1N1 virus known as vaccine associated enhanced respiratory disease (VAERD). Pigs in the VAERD-affected group demonstrated more severe clinical signs that included coughing, respiratory distress, anorexia and lethargy in addition to elevated body temperatures compared to naive-challenged pigs. Microscopic and macroscopic pneumonia and lung lesion scores were significantly elevated in the VAERD group with increased concentrations of pulmonary pro-inflammatory cytokines. Lung lesions at 1 and 2 days post inoculation (dpi) consisted of severe necrotizing bronchitis and bronchiolitis with interlobular and alveolar edema, hemorrhage and suppurative alveolitis. Marked peribronchiolar lymphocytic cuffing and interstitial pneumonia were consistent pathological features in the lung of VAERD-affected pigs at 5 dpi. Trachea lesions in vaccinated/challenged pigs consisted of suppurative and lymphocytic tracheitis and epithelial necrosis compared to mild lesions demonstrated in non-vaccinated/challenged pigs. The immune response to the inactivated vaccine consisted of hemagglutination inhibition (HI) and serum neutralizing (SN) antibodies to homologous virus that did not cross-react with the challenge virus. In contrast, whole virus, anti-pH1N1 IgG antibodies were detected in the serum and lung of VAERD-affected pigs. However, a cross-reactive mucosal IgA response was not detected in the lung in pigs primed with the inactivated vaccine. VAERD-affected pigs demonstrated a post-challenge primary immune response consisting of anti-pH1N1 HI, SN and ELISA antibodies to the challenge virus. The results of these studies establish a consistent swine model of VAERD using an inactivated influenza vaccine followed by challenge with heterologous virus. The coincidental increase in inactivated influenza vaccine use and the evolving antigenic diversity of influenza A viruses in swine creates a realistic potential for vaccine/challenge mismatch.