Background and Purpose: Social determinants of health (SDOH) have been previously associated with incident stroke. Although SDOH often cluster within individuals, few studies have examined associations between incident stroke and multiple SDOH within the same individual. The objective was to determine the individual and cumulative effects of SDOH on incident stroke. Methods: This study included 27 813 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study, a national, representative, prospective cohort of black and white adults aged ≥45 years. SDOH was the primary exposure. The main outcome was expert adjudicated incident stroke. Cox proportional hazards models examined associations between incident stroke and SDOH, individually and as a count of SDOH, adjusting for potential confounders. Results: The mean age was 64.7 years (SD 9.4) at baseline; 55.4% were women and 40.4% were blacks. Over a median follow-up of 9.5 years (IQR, 6.0–11.5), we observed 1470 incident stroke events. Of 10 candidate SDOH, 7 were associated with stroke ( P <0.10): race, education, income, zip code poverty, health insurance, social isolation, and residence in one of the 10 lowest ranked states for public health infrastructure. A significant age interaction resulted in stratification at 75 years. In fully adjusted models, among individuals <75 years, risk of stroke rose as the number of SDOH increased (hazard ratio for one SDOH, 1.26 [95% CI, 1.02–1.55]; 2 SDOH hazard ratio, 1.38 [95% CI, 1.12–1.71]; and ≥3 SDOH hazard ratio, 1.51 [95% CI, 1.21–1.89]) compared with those without any SDOH. Among those ≥75 years, none of the observed effects reached statistical significance. Conclusions: Incremental increases in the number of SDOH were independently associated with higher incident stroke risk in adults aged <75 years, with no statistically significant effects observed in individuals ≥75 years. Targeting individuals with multiple SDOH may help reduce risk of stroke among vulnerable populations.