The objective of this study was to compare the virulence of three different porcine circovirus type 2 (PCV2) genotypes (PCV2a, PCV2b, and PCV2d) in pigs infected with either one of these three PCV2 genotypes versus pigs dually inoculated with Mycoplasma hyopneumoniae and PCV2. Pigs were inoculated intratracheally with M. hyopneumoniae at 4 weeks of age followed by another intranasal inoculation at 6 weeks of age with one of three PCV2 genotypes. Dual infection with two pathogens produced moderate and severe dyspnea, lethargy, and reduced weight gain in pigs regardless of the PCV2 genotype evaluated compared with pigs only inoculated with PCV2. The overall levels of PCV2d viremia and severity of lymphoid lesions, and PCV2-antigen within lymphoid lesions were significantly higher in pigs dually inoculated with M. hyopneumoniae/PCV2d when compared with all other dually inoculated groups. The level of PCV2 viremia and the production of PCV2-associated lymphoid lesions did not differ significantly among PCV2a, PCV2b, and PCV2d single-inoculated pig groups. The results of this study demonstrated that M. hyopneumoniae potentiated the replication of PCV2d more than it did with the other PCV2 genotypes as measured by lymphoid lesion severity.