PURPOSE: The hypothesis that vitamin supplementation may prevent cardiovascular disease (CVD) has been supported by compelling mechanistic and observational data. However, most large-scale randomized controlled trials (RCT) of vitamins and CVD are null, leading to the conclusion that vitamins have no role in CVD prevention. Our objective was to examine challenges inherent in single nutrient trials using vitamin D and CVD as a case study. METHODS: We conducted a systematic scoping review of the literature published since 2011 on vitamin D and CVD, including RCTs, prospective cohort studies (PCS) and systematic reviews from Medline, Web of Science and Cochrane. Studies were conducted in adults and included CVD outcomes with a minimum sample of 500 for RCTs and 10,000 for PCS. We applied Bradford Hill criteria for the establishment of causality in biological systems. RESULTS: The search yielded 4170 papers, of which 40 were eligible, including 6 RCTs and 7 PCS. The Bradford Hill analysis of a causal relationship between vitamin D and CVD was mixed, with strong mechanistic support and reasonable strength and consistency in observational data but weak evidence of temporality. There was sufficient justification for trialling a benefit for CVD prevention but RCTs were inconsistent with the mechanistic and observational studies and reported mostly null results. Contextual factors were key, including baseline vitamin D status among participants, background supplementation and underlying participant disease profiles. CONCLUSION: This example illustrates the complexity of conducting nutrient trials and raises questions about RCTs of single nutrients for complex chronic diseases. The core challenge common to all nutrient trials is the absence of a zero-intake placebo group and variable background exposures. Alternative approaches and interpretation paradigms are required.