Pneumonia associated with porcine circovirus type 2 (PCV2) is being diagnosed in an increasing number of respiratory disease cases in growing swine. Multiple viral infections are commonly diagnosed in cases of porcine respiratory disease complex (PRDC) at the Iowa State University Veterinary Diagnostic Laboratory. In the year 2000, porcine reproductive and respiratory syndrome virus (PRRSV) was present in 42% of these cases, PCV2 was present in 22%, swine influenza virus (SIV) was present in 19%, and Mycoplasma hyopneumoniae was present in 22%. In this report, three clinical cases are described in which there were concurrent infections with PCV2 and PRRSV, PCV2 and SIV, and PCV2 and M hyopneumoniae. Prolonged and unusually severe clinical disease, unique histologic lesions of lymphoid depletion and airway fibrosis, and abundant PCV2 antigen within these lesions suggest that PCV2 is playing a pathogenic role in PRDC.