Objective: Previous studies suggested that insulin resistance (IR) may be a significant causal risk factor for cardiovascular events and depression independent of other risk factors. In this prospective, we assess the value of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at admission to predict post-stroke depression (PSD) later developed at 3 months follow-up. Methods: This prospective, multicenter cohort study was conducted from January 2015 through December 2016 in China. Clinical information and HOMA-IR was assessed at admission. Neurological and neuropsychological evaluations were conducted at the 3-month follow-up. Results: In the study population, 56.6% were male and the median age was 59 years (interquartile range [IQR]: 51-69). One hundred and eighty-six patients (26.6%) showed depression at 3 months after admission and in 53 patients (28.5%) this depression was classified as severe. For each 1-unit increase of HOMA-IR, the unadjusted and adjusted risk of PSD increased by 63% (odds ratios [OR]: 1.63; 95% confidence interval [CI]: 1.44-1.85; P < 0.001) and 27% (1.27; 1.13-1.39; P = 0.002). In a multivariate model using the fourth quartiles of HOMA-IR vs. quartiles 1 through 3 together with the clinical variables, the marker displayed prognostic information (PSD: OR for fourth quartile, 2.76 [95% CI, 1.66-3.73; P = 0.003]). Conclusions: The data suggests that the HOMA-IR may be of potential clinical relevance in identifying stroke patients at risk of developing depression, independent of the well-established predictors.