Background: Vaccination with 7-valent pneumococcal conjugate vaccine (PCV) has been shown to decrease the incidence of recurrent invasive pneumococcal disease among HIV-infected adults in Africa. Longitudinal follow-up studies of serologic responses to different doses of 7-valent PCV are rarely performed in HIV-infected adult patients receiving combination antiretroviral therapy (cART). Methods: From October 2008 to June 2010, 115 CD4-matched pairs of HIV-infected patients aged ≥20 years who had no prior pneumococcal vaccination received one or two doses of 7-valent PCV. Anticapsular antibodies against 4 serotypes (6B, 14, 19F, and 23F) were examined at the 12th, 24th, 36th, and 48th week following vaccination. Significant antibody responses were defined as ≥2-fold increase in the IgG level plus a post-vaccination antibody level ≥1000 ng/ml. Results: The most common reported adverse effects were injection site soreness (19.3%) and pain (4.8%). Significant antibody response rate was highest for serotype 14, followed by 23F, 19F, and 6B in all of the four time points examined. At week 48, patients who received two doses of 7-valent PCV had a significantly higher response rate to serotype 6B (P = 0.03) and 23F (P = 0.01) than those who received one dose; moreover, the former group also had a higher response rate to at least one (P = 0.03) and two serotypes (P = 0.02) in intention-to-treat analysis than the latter group. Conclusions: HIV-infected adult patients on cART who received two doses of 7-valent PCV achieved better serological responses to at least one serotype than those who received one dose during the 48 weeks of follow-up.