Due to the ubiquitous nature of porcine circovirus type 2 (PCV2) in the pig population and the increasing use of PCV2 vaccines in breeding herds, the majority of dams have been exposed to field PCV2 or PCV2 vaccines, resulting in piglets with varied levels of passively acquired PCV2 maternal antibodies. The objective of the current research was to investigate the influence of passively acquired anti-PCV2 antibodies on PCV2 vaccine efficacy. Sixty 26-day-old pigs were divided into four groups: vaccinated pigs with no maternal PCV2 antibodies at the time of vaccination (VAC-NEG; n = 9), vaccinated pigs with maternal PCV2 antibodies at the time of vaccination (VAC-POS; n = 21), nonvaccinated pigs with no maternal antibodies at the time of challenge (NVAC-CNEG; n = 15), and nonvaccinated pigs with maternal antibodies at the time of challenge (NVAC-CPOS; n = 15). Vaccinations and challenges were performed on trial days 0 and 28, respectively, according to group designation. The pigs were monitored for clinical signs of disease daily and weighed weekly, and blood was collected weekly. All pigs were necropsied on trial day 49, and tissues were evaluated for macroscopic and microscopic lesions. Serum was evaluated using PCV2 immunoglobulin G (IgG) and PCV2 IgM enzyme-linked immunosorbent assays, quantitative PCV2 PCR, and a serum PCV2 neutralizing antibody test. In comparison to NVAC-CPOS pigs, VAC-POS animals had significantly (P <0.01) less severe microscopic PCV2-associated lymphoid lesions and significantly (P <0.04) reduced PCV2 genomic copies in serum following PCV2 challenge. These results indicate that vaccination with Suvaxyn PCV2 One Dose reduces viremia and prevents microscopic lesions associated with PCV2 in the presence of maternal antibodies.