Background <p>Dyslipidemia and poor immune reconstruction are mutually causal in HIV/AIDS patients. However, the predictive value of dyslipidemia for poor immune reconstruction remains a subject of debate. This study aims to assess the predictive value of specific blood lipid levels for poor immune reconstitution and changes in lipid profiles in HIV/AIDS patients.</p> Methods <p>The lipids level of 429 HIV/AIDS patients were measured, and patients were treated with antiretroviral therapy (ART) and followed up. The cohort was stratified into two groups based on immune function. Logistic regression analyses and receiver-operating characteristic (ROC) curves were employed to confirm the independent prognostic factors influencing immune reconstitution outcome. Sensitivity analyses were conducted across different subgroups.</p> Results <p>At the conclusion of the follow-up period, the rate of overall immunological non-responders (INR) was 21.0%. The incidence of baseline dyslipidemia was higher in the INR group, with high-density lipoprotein cholesterol (HDL-C) being the primary contributor. Total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels increased significantly after 24 months of viral suppression (<i>P</i> &lt; 0.05), with a greater percentage increase in TC observed in the INR group. Logistic regression analysis revealed that HDL-C was a significant predictor of INR (OR = 0.247, 95% CI = 0.088–0.696, <i>P</i> = 0.008). Sensitivity analyses confirmed the robustness of the associations between HDL-C and poor immune reconstitution across various subgroups.</p> Conclusion <p>Baseline HDL-C level can serve as a prognostic marker for poor immune reconstitution in HIV/AIDS patients, and INR are more likely to exhibit elevated TC levels. Early lipid profile assessment could inform clinical management strategies, thereby improving better immune outcomes in this vulnerable population.</p> Clinical trial number <p>Not applicable.</p>