Objective To delineate the distinct immunometabolic perturbations in HIV-associated acute exacerbation of chronic obstructive pulmonary disease (HIV-AECOPD) and to identify circulating biomarkers predictive of short-term prognosis.Methods An integrated proteomic and metabolomic discovery analysis was conducted on plasma from patients with HIV-AECOD, AECOPD alone, and healthy controls (n = 5 per group). Key differentially expressed molecules were subsequently validated via targeted assays in a larger, independent cohort (n = 20 per group). The prognostic value of validated biomarkers for 3-month poor outcomes was evaluated using a Random Forest model and receiver operating characteristic (ROC) curve analysis.Results Multi-omics discovery revealed a unique plasma profile in HIV-AECOPD, characterized by dysregulated humoral immunity, complement activation, neutrophil extracellular trap formation, and metabolic reprogramming. Validation assays were performed for six candidate biomarkers (CRP, SAA, IgG, TG, C3, and C4). Among these, CRP emerged as the most important predictor of poor 3-month prognosis (Random Forest Mean Decrease Gini = 1.33), demonstrating significant predictive value (AUC = 0.8125, 95% CI: 0.628–0.997).Conclusions This study defines a specific immunometabolic signature in HIV-AECOPD and nominates CRP as a potential biomarker for risk-stratifying patients at high risk of adverse short-term outcomes, offering both mechanistic insight and a candidate tool for clinical prognostication.