OBJECTIVE: To examine US physicians' self-reported knowledge about the Polypill, factors considered in deciding whether to prescribe it, and acceptance of prescribing it for cardiovascular disease (CVD) prevention. METHODS: Numerical scales of 0 (lowest) to 5 (highest) were used to assess self-reported knowledge and importance of factors relevant to making a decision to prescribe a Polypill. Characteristics of physicians indicating they would prescribe a Polypill were compared. RESULTS: Among 952 physicians surveyed February through March 2010, mean self-rated knowledge about the Polypill was 2.0±1.5. Importance of degree of CVD event reduction, cost, and side effects were rated with means of 4.4, 4.3, and 4.3, respectively. 83% of respondents indicated they would "definitely" or "probably" prescribe it for high-risk patients; 62% would do so for moderate risk patients. Physicians with self-rated knowledge at ≥75th percentile were more likely to indicate they would prescribe a Polypill for moderate risk (adjusted OR 2.16; 95% CI 1.60-2.93) and high-risk (adjusted OR 1.57; 95% CI 1.07-2.32) patients. CONCLUSION: Among this sample of physicians, there is relatively high acceptance of prescribing a Polypill for CVD prevention despite relatively modest knowledge about it.