Background and AimsCardiovascular diseases (CVDs) are one of the major diseases in developing and developed countries and have high prevalence and mortality rates. Pharmacological interventions, especially the use of combination medications, can have preventive effects in patients with CVDs. Recently, in the PolyIran trial, a combination of atorvastatin, hydrochlorothiazide, aspirin, and valsartan or enalapril (Polypill) was shown to be effective in providing survival benefits as a primary prevention strategy. In the present study, we examine the cost‐effectiveness of the use of polypill compared to its individual components (named as medication monotherapy) in the prevention of CVDs in Iran.MethodsThis was an economic evaluation study conducted to compare the cost‐utility of polypill with that of medication monotherapy for 10,000 hypothetical cohorts of people over 35 years of age using the Markov model and with a lifetime horizon. The study perspective was patient perspective and direct medical costs, quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratio were estimated. To deal with uncertaintysensitivity analyses were used.ResultsThe results showed that polypill, with the lowest costs (871 USD) and highest QALYs (14.55), had the most cost‐utility than medication monotherapy. Also, the results showed that the highest sensitivities were related to the utilities of angina and stroke states. At the 21,768 USD threshold, polypill had a 92% probability of being cost‐effective versus other medications.ConclusionConsidering that polypill had the most cost‐utility, it is suggested that health system policymakers pay special attention to polypill in designing clinical guidelines. Also, through covering this medication by health insurance organizations, it is possible to complete the country's medicine pharmacopeia in preventing CVDs.