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Background: Large-scale trials have not supported a role of vitamin E supplementation in reducing the risk of cardiovascular disease (CVD). We investigated whether baseline diet quality and vitamin E intake modified the effect of randomized vitamin E supplementation on the risk of CVD in the Physicians’ Health Study II (PHS II).Methods: The PHS II was a randomized, double-blind, placebo-controlled trial testing 400 IU synthetic α-tocopherol on alternate days. 14,641 men aged ≥50 years were included. 13,316 men (91%) completed a 116-item food frequency questionnaire and were included in our intention-to-treat analysis. We examined effect modification by baseline diet quality as assessed by dietary patterns (tertiles of the Alternate Healthy Eating Index [AHEI] and Alternate Mediterranean Diet [AMED]), and by dietary and supplemental vitamin E intake.Results: During a mean 8.0 years of follow-up, baseline diet quality or vitamin E intake did not modify the effect of vitamin E use on the primary endpoint of major CVD events (Table). However, AHEI modified the effect of randomized vitamin E use on the secondary endpoint of MI (P, interaction=0.02), with a statistically significant 39% lower risk among men in the lowest tertile of the AHEI. A similar and statistically significant 37% lower risk of MI was observed in the lowest category of the AMED (P, interaction=0.08). There was no evidence that diet quality modified the effect of vitamin E use on risks of stroke or CVD mortality, and baseline dietary and supplemental vitamin E intake did not modify the effects on any outcome.Conclusion: Diet quality did not modify the effect of vitamin E supplementation on most CVD outcomes but did modify its effect on MI. Given concerns about multiple comparisons and the need for replication, our findings should be interpreted with caution.