Context: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) induce oxidative stress, highlighting the need for bio-oxidative alternatives. Aims: To evaluate the effects of two consecutive cycles of medical ozone therapy in HIV-seropositive patients and compare the results of both cycles using clinical indicators and redox biomarkers. Methods: A quasi-experimental study was conducted following a research protocol, including 25 HIV-seropositive patients undergoing ART, who received medical ozone therapy via rectal insufflation (volumes of 150-300 mL in a stepwise manner) in 12 sessions over one month, with two cycles spaced three months apart. The initial and final evaluation included hematological and biochemical laboratory tests, absolute T-CD4+ lymphocyte count, viral load, and seven plasma redox balance indicators. Final variable values were compared with baseline values and a supposedly healthy individual group (SHIG). Adverse reactions were recorded. Results: ART showed beneficial effects in 78% of cases, with no significant differences in hematological and biochemical variables (p>0.05) between the treated group at the beginning and end of the study. Significant differences (p<0.05) were observed in the mean values of malondialdehyde concentration, reduced glutathione, hydroperoxides, advanced oxidation protein products, and peroxidation potential at the end of the study compared to baseline values and SHIG. Conclusions: The beneficial effects of two cycles of medical ozone therapy combined with ART demonstrated a 74% simultaneous modification in reducing oxidation of proteins and lipids and an increase in cellular immune indicators in the studied patients. No hematological or blood toxicity, adverse events, or drug interactions were observed.