Background: Few large-scale randomized trials have investigated whether supplemental vitamin D at doses above those currently recommended for bone health reduces the risk of cancer, cardiovascular disease (CVD), or other conditions. The VITamin D and OmegA-3 TriaL (VITAL) was designed to fill this gap. This presentation provides an integrated overview of the intervention-phase results of the vitamin D component of the main trial and its ancillary studies. Methods: VITAL was a nationwide, randomized, placebo-controlled, 2x2 factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) for a median of 5.3 years for primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55 years, including 5,106 Black individuals. Participants were not selected on the basis of baseline vitamin D status. Ancillary studies investigated treatment effects on fracture, autoimmune disease, cognition, depression, respiratory diseases, and other outcomes. Studying the influence of age, sex, race and ethnicity, body mass index (BMI), and baseline 25-hydroxyvitamin D status on treatment effects was a prespecified goal. Results: Vitamin D did not significantly reduce the primary endpoint of invasive cancer incidence (hazard ratio [HR]=0.96 [95% confidence interval 0.88-1.06]) but showed a signal for reduced cancer mortality (HR=0.83 [0.67-1.02]), especially in prespecified analyses that accounted for latency (HR=0.75 [0.59-0.96] excluding the first two years of follow-up), as well as a significant reduction in advanced-stage (metastatic or fatal) cancer over the full duration of follow-up (HR=0.83 [0.69-0.99]; p=0.04). Vitamin D did not reduce the co-primary endpoint of major CVD events (HR=0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR=0.99 [0.87-1.12]). Vitamin D reduced risk of autoimmune disease (HR=0.78 [0.61-0.99]), with the protective effect strengthening after two years (HR=0.61 [0.43-0.86]), but was unrelated to fractures and other ancillary endpoints. Variation in intervention effects by BMI was observed for multiple outcomes, with greater benefits in individuals with healthy weight than in those with overweight or obesity. Effect modification by other prespecified participant characteristics was more limited. Conclusion. Vitamin D reduced risk of advanced cancer and autoimmune disease but not other health conditions examined in the overall cohort. BMI modified treatment-associated effects for several endpoints. The findings do not support routine vitamin D supplementation of healthy adults for prevention of chronic disease but suggest that understanding the role of BMI may inform targeted recommendations for supplement use. Further study is needed to confirm observed benefits for advanced cancer and autoimmune disease and determine which individuals are most likely to benefit from supplementation. VITAL clinicaltrials.gov identifier: NCT01169259