Objective <p>This retrospective case-control study examined lipid and homocysteine (Hcy) patterns in Tibetan patients with acute ischemic stroke (AIS) in Xizang and developed an exploratory model to distinguish AIS cases from controls.</p> Methods <p>We enrolled 549 Tibetan AIS patients and 559 age- and sex-matched Tibetan controls. Clinical and biochemical indicators were compared between groups. XGBoost feature importance was used only for exploratory feature selection, and a random forest model was then constructed to evaluate the case-control discriminative ability of the selected indicators. Model performance was internally evaluated using AUC, recall rate, and F1 score.</p> Results <p>Compared with controls, AIS patients had lower high-density lipoprotein cholesterol (HDL), lower total cholesterol (TC), and higher Hcy levels. The combined lipid-Hcy imbalance pattern was defined as the co-occurrence of lower HDL and TC levels and higher Hcy levels in AIS patients than in controls. HDL, TC, and Hcy were consistently selected as AIS-associated indicators. The optimized random forest model based on these three indicators achieved an AUC of 0.924 in cross-validation and 0.887 in the test set.</p> Conclusion <p>HDL, TC, and Hcy were associated with AIS case-control status in Tibetan participants from Xizang and should be interpreted as associative markers rather than causal factors or diagnostic biomarkers. Because this was a retrospective case-control study and biomarkers were measured after AIS onset in cases, the model demonstrates only internal case-control discrimination and does not establish pre-onset predictive value. Prospective, multi-center external validation is needed before clinical use.</p>