<b><i>Background:</i></b> Previous studies reported an association of renal impairment with stroke, but there are uncertainties underpinning this association. <b><i>Aims:</i></b> We explored if the association is explained by shared risk factors or is independent and whether there are regional or stroke subtype variations. <b><i>Methods:</i></b> INTERSTROKE is a case-control study and the largest international study of risk factors for first acute stroke, completed in 27 countries. We included individuals with available serum creatinine values and calculated estimated glomerular filtration rate (eGFR). Renal impairment was defined as eGFR <60 mL/min/1.73 m<sup>2</sup>. Multivariable conditional logistic regression was used to determine the association of renal function with stroke. <b><i>Results:</i></b> Of 21,127 participants, 41.0% were female, the mean age was 62.3 ± 13.4 years, and the mean eGFR was 79.9 ± 23.5 mL/min/1.73 m<sup>2</sup>. The prevalence of renal impairment was higher in cases (22.9% vs. 17.7%, <i>p</i> < 0.001) and differed by region (<i>p</i> < 0.001). After adjustment, lower eGFR was associated with increased odds of stroke. Renal impairment was associated with increased odds of all stroke (OR 1.35; 95% CI: 1.24–1.47), with higher odds for intracerebral hemorrhage (OR 1.60; 95% CI: 1.35–1.89) than ischemic stroke (OR 1.29; 95% CI: 1.17–1.42) (<i>p</i><sub>interaction</sub> 0.12). The largest magnitudes of association were seen in younger participants and those living in Africa, South Asia, or South America (<i>p</i><sub>interaction</sub> < 0.001 for all stroke). Renal impairment was also associated with poorer clinical outcome (RRR 2.97; 95% CI: 2.50–3.54 for death within 1 month). <b><i>Conclusion:</i></b> Renal impairment is an important risk factor for stroke, particularly in younger patients, and is associated with more severe stroke and worse outcomes.