The aim of this study was to evaluate the protective efficacy of the CIRCOQ porcine circovirus type 2 (PCV2) subunit vaccine in piglets with high maternally derived antibodies (MDAs) against disease caused by natural infection with PCV2d. A total of 130 weaned, 21-day-old healthy pigs was allocated into 3 trial groups. The signs of respiratory disorder were higher in unvaccinated pigs than in vaccinated pigs at 13 to 17 weeks old (P < 0.05), 18 to 22 weeks old (P < 0.001), and 23 to 27 weeks old (P < 0.01). The unvaccinated pigs had an early rate of dermatitis at 8 to 12 weeks old (10.0%), 13 to 17 weeks old (30.0%), 18 to 22 weeks old (46.7%), and 23 to 27 weeks old (33.3%), while there were no cases of dermatitis in vaccinated pigs. There was a significant difference (P < 0.05) in the mortality of pigs in the unvaccinated group and the 2-dosed vaccinated group. PCV2 viremia was detected in the blood and peaked at 105 days old in both unvaccinated pigs (Ct-adj = 8.40) and pigs vaccinated with 1 dose (Ct-adj = 6.37), while no detectable PCV2 virus was found in the blood of pigs vaccinated with 2 doses. At 77 and 105 days old, the PCV2 viremia load (Ct-adj) of unvaccinated pigs and those vaccinated with 1 dose was significantly higher (P < 0.05) than that of the 2-dosed vaccinated pigs. The body weight (BW), average weight gain (AWG), and average daily gain (ADG) in both groups of vaccinated pigs were significantly higher (P < 0.05) than those of unvaccinated pigs. The study vaccine was significantly efficacious in protecting vaccinated pigs against clinical symptoms, blood viral load, and mortality, as well as improving productivity, compared with unvaccinated pigs.