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Background: Patients with cardiovascular diseases (CVD) are at high risk of experiencing drug–drug interactions (DDIs). The objective of this study was to evaluate the frequency, level and risk factors associated with potential-DDIs (pDDIs) in hospitalized CVD patients at cardiology departments of two tertiary care hospitals in Quetta, Pakistan. Methods: In the current prospective observational study, a total of 300 eligible CVD inpatients were evaluated for pDDIs using Lexicomp Interact®. The pDDIs were classified into class A (no known interaction); B (no action needed); C (monitor therapy: it is documented that the benefits of an interaction outweigh the risk, appropriately monitor therapy in order to avoid potential adverse outcomes); D (consider therapy modification: it is documented that proper actions must be taken to reduce the toxicity resulting from an interaction); X (avoid combination: the risk of an interaction outweighs the benefits and are usually contraindicated). Multivariate binary logistic regression analysis was used to find factors associated with the presence of Class-D and/or X pDDIs. A p-value < 0.05 was considered statistically significant. Results: With a median of 8.50 pDDIs per patient, all patients (100%) had ≥ 1 pDDIs. Out of total 2787 pDDIs observed, 74.06% (n = 2064) were of moderate and (n = 483) 17.33% of major severity. Class C pDDIs were most common (n = 1971, 70.72%) followed by D (n = 582, 20.88%), B (n = 204, 7.32%) and X (n = 30, 1.08%). Suffering from cardiovascular diseases other than myocardial infarction (OR 0.053, p-value < 0.001) and receiving > 12 drugs (OR 4.187, p-value = 0.009) had statistical significant association with the presence of class D and/or X pDDIs. Conclusion: In the current study, pDDIs were highly prevalent. The inclusion of DDI screening tools, availability of clinical pharmacists and paying special attention to the high-risk patients may reduce the frequency of pDDIs at the study sites. [ABSTRACT FROM AUTHOR]