Vitamin D deficiency is widespread and has been linked to adverse health outcomes, but its causal role remains debated. We analyzed data from two large healthcare networks-Leumit Health Services in Israel and the US-based TriNetX network-using matched cohort designs to compare individuals with severe vitamin D deficiency (<10 ng/mL) to those with sufficient levels (>30 ng/mL). Vitamin D showed strong seasonal variation, and deficiency was associated with increased risks of mortality, cardiovascular events, dialysis, and leg/foot amputation in both cohorts. To assess causality, we modeled serum vitamin D levels based on monthly pharmacy-dispensed supplementation and performed time-dependent Cox regressions adjusting for baseline deficiency. We identified a dose-dependent reduction in risk with supplementation associated, independent of baseline levels, with substantial absolute risk reductions. These findings support vitamin D deficiency as a modifiable risk factor and provide a rationale for targeted clinical trials in severely deficient populations.