This study aimed to determine the relationship between the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio and adverse outcomes in patients with first-ever ischemic stroke (IS), and to validate its potential as a prognostic indicator.

A dual-cohort study integrating retrospective and prospective designs was conducted. The retrospective cohort included 45,162 patients with first-ever IS, and the prospective cohort comprised an independent sample of 2151 patients with first-ever IS. The primary outcome was a composite of stroke recurrence or all-cause death within five years. In the retrospective cohort, logistic regression and regression discontinuity design (RDD) were used to assess the relationship between TC/HDL-C ratio and adverse outcomes, adjusting for confounding factors (e.g., age, sex, comorbidities, and medication use). In the prospective cohort, logistic regression was employed to validate the association, with Kaplan-Meier survival analysis used to characterize prognosis across TC/HDL-C subgroups. Odds ratio (OR) and 95% confidence interval (CI) were calculated.

In the retrospective cohort, a higher TC/HDL-C ratio was identified as an independent risk factor for Five-year adverse outcomes (univariate analysis: OR 1.35 (95% CI, 1.28–1.42), P < 0.001; multivariate analysis: OR 1.30 (95% CI, 1.22–1.39), P < 0.001), and this association was confirmed by RDD. In the prospective cohort, logistic regression replicated these findings, with each unit increase in TC/HDL-C associated with a 12% higher risk of adverse outcomes [OR 1.12 (95% CI, 1.02–1.23), P < 0.05]. Kaplan-Meier analysis further showed that patients with lower TC/HDL-C ratios had significantly longer event-free survival over the 5-year follow-up (log-rank P < 0.001).

Elevated TC/HDL-C ratio is independently associated with an increased risk of stroke recurrence or death within 5 years in patients with first-ever IS. These findings support the utility of the TC/HDL-C ratio as a clinically relevant prognostic marker for long-term outcomes in IS patients.