Anecdotal information from producers and veterinarians in the field suggests that there are differences in susceptibility to porcine circovirus type 2 associated disease (PCVAD). Some producers have changed breeding programs based on this information. The objective of this study was to conduct a controlled experiment and determine if there are differences in susceptibility to porcine circovirus type 2 (PCV2) based on serum antibody levels, PCV2-associated microscopic lesions, selected cytokine levels, and amount of PCV2 DNA in experimentally inoculated conventional Landrace and Pietrain pigs. Those breeds were selected based on information from the field that Landrace pigs seemed more susceptible and Pietrain less susceptible to PCVAD. Thirty-nine Landrace piglets and 39 Pietrain piglets were blocked by breed, sire, dam, and litter and randomly divided into the following four groups: Landrace-NEG (n = 13; Landrace), Pietrain-NEG (n = 13; Pietrain), Landrace-PCV2 (n = 26; Landrace), and Pietrain-PCV2 (n = 26; Pietrain). After waning of passively acquired anti-PCV2 antibodies, Landrace-PCV2 and Pietrain-PCV2 groups were inoculated with PCV2 isolate ISU-40895. Landrace-NEG and Pietrain-NEG groups were housed in a separate room, remained non-inoculated, and served as controls. All pigs in all groups were necropsied at 24 weeks of age or 21 days post PCV2-inoculation. Onset of seroconvserion and levels of anti-PCV2-IgM and IgG antibodies were similar in Landrace-PCV2 and Pietrain-PCV2 groups. Similarly, amount of PCV2 DNA and cytokine levels in serum samples was not different between the two PCV2-inocualted groups. The most striking difference between Landrace and Pietrain pigs was the severity of PCV2-associated microscopic lesions with Landrace-PCV2 pigs developing significantly (P < 0.05) more severe lesions compared to Pietrain-PCV2 pigs. Interestingly, although the pigs originated on the same farm where their dams were co-mingled, passively-acquired anti-PCV2-antibodies waned in Pietrain pigs by approximately 12 weeks of age whereas the majority of the Landrace pigs remained PCV2 seropositive until 18 weeks of age. Contact Information: [email protected]