Background and Aim: Drug-Drug Interactions (DDIs) can lead to decreased therapeutic efficacy, the occurrence of serious complications, and even mortality in patients. In the intensive care unit (ICU), the likelihood of these interactions increases due to the administration of a greater number of medications. Therefore, the present study aims to investigate the frequency, severity, and risk factors associated with DDIs in hospitalized patients in the ICUand its results may contribute to improving therapeutic management and reducing complications arising from DDIs. Materials and Methods: This cross-sectional study was conducted on 79 hospitalized patients in the ICUs of Shohadaye Ashayer Hospital in Khorramabad city from March 21, 2021, to June 21, 2021. To identify drug interactions, three online drug databases—Medscape, Epocrates and Drugs.com—were utilized. Data analysis was performed using SPSS version 21. Results: The median length of hospital stay was 11 days with interquartile range (IQR) of 15 days (mean ± standard deviation: 14.29 ± 11.67 days). In the intensive care unit (ICU), the median length of hospital stay was approximately 7 days and IQR was 11 days (mean ± standard deviation: 11.32 ± 10.87 days). Also, the mean number of medications used per patient was 18.08 ± 8.09. In this study, there was a significant correlation between the number of DDIs and various factors such as the duration of hospitalization and the ICU and the number of medications consumed (P<0.001). Also, no significant correlation was observed between DDIs and patients' age. Conclusion: By educating healthcare personnel about potential DDIs and their adverse effects, replacing high-interaction Drugs with alternative options, and utilizing interaction detection software, it is possible to effectively prevent DDIs and harm to patients while reducing treatment costs.