Porcine circovirus type 2 (PCV2) causes a number of diseases including PMWS. The number of pigs that are infected with PCV2 that go on to clinical disease is extremely variable. The exact mechanism that causes PCV2 infection to result in disease is currently unknown. Currently, inducing clinical disease associated with PCV2 under laboratory conditions has been unreliable. Work in our laboratory had shown that the virus replicates in monocytes and replicating lymphocytes. In this study, we proposed to assess the replication of the virus in lymphocytes from tissue and blood from pigs concurrently infected with PCV2 and Mycoplasma hyopneumoniae (MHYO). We chose this model as we had previously observed an increase in the number of pigs exhibiting PCV2 associated disease when co-infected with MHYO in addition to PCV2. In this study, we studied the ability of lymphocytes to proliferate and the amount of virus produced in the presence of PCV2 with and without MHYO compared to non-infected pigs. Pigs from each group were sacrificed at 7, 14, and 21 days following PCV2 infection. While we confirmed that pigs in the appropriate groups were infected with either PCV2 and/or MHYO based on pneumonia, serology and the presence of virus, no clinical disease or symptoms occurred. The lymphoid depletion, which is a hallmark of PCV2 disease, was also extremely mild, although we demonstrated the presence of virus in the tissues. No alterations in the lymphocyte populations or their ability to proliferate and respond to antigen were observed in this study. This study did show that in the absence of clinical disease, PCV2 does not appear to suppress or modulate the immune system. More work needs to be done to identify why some pigs, such as in this study, remain healthy in the presence of MHYO and PCV2 and others go on to develop clinical disease that typically results in death.