The aim of this study was to evaluate the long-term effectiveness of first-line antiretroviral therapy in HIV/AIDS patients in Southeast China. A total of 450 eligible patients were selected to initiate first-line antiretroviral therapy from February 2005 through August 2009. During the study period from 2009 through 2013, each subject received clinical and laboratory monitoring for effectiveness, safety and toxicity once every 3 months in the first year, and once every 6 months in the following years. The response to first-line antiretroviral therapy was evaluated through body weight gain and immunological and virological outcomes. During the mean follow-up period of 70.86 ± 28.9 months, the overall mortality was 14.2%. The mean body weight and CD4(+) counts increased significantly following antiretroviral therapy as compared to baselines across the follow-up period, and the rate of immunological effectiveness was over 85% in all subjects at 2 to 5 years of treatment. The rate of inhibition of HIV virus was 87.67%, 89.32%, 91.73%, 92.8% and 91.63% across the study period. In addition, significant differences were detected after treatment as compared to baselines, and Pearson correlation analysis revealed a positive correlation between immunological effectiveness and viral inhibition. Forty-eight percent of the subjects changed antiretroviral drugs once, and 16.22% twice, and 31 patients switched from first-line to second-line antiretroviral therapy. Long-term antiretroviral therapy remains effective for treatment of HIV/AIDS, resulting in higher mean body weight, effective viral inhibition and a higher CD4 count. Immunological effectiveness of antiretroviral therapy positively correlates with HIV viral inhibition.