Context: Intensive care unit (ICU) patients suffer from various comorbidities and usually receive complex pharmacotherapy which increases the risk of drug–drug interactions (DDIs). Aim: To identify and assess potential DDIs (pDDIs) in ICU patients. Settings and design: A prospective observational study conducted in ICU of a tertiary care hospital for a period of 6 months. Materials and methods: Patient information was noted in the data collection form and pDDIs were assessed using Micromedex® database. Statistical analysis used: Chi-square test was used to find correlation of pDDIs with patient parameters. p value was calculated keeping the significance level 0.05. Results: Total 400 subjects were included; having an average age of 55.99 ± 15.62 years with a higher percentage of males (61.75%). About 305 (76.25%) patients were found with pDDIs, showing an average of 2.93 pDDIs/patient. The findings of this study were as follows: Total interactions = 1171, contraindicated = 6 (1%), major = 715 (61%), moderate = 428 (36%), and minor = 22 (2%) pDDIs. Further, majority of pDDIs had onset of action “not specified”; documentation “fair” and probable mechanism “pharmacodynamic” in nature. Significant association of occurrence of pDDIs was found with number of drugs prescribed to patients in ICU. Conclusion: This study demonstrated a high prevalence of pDDI in ICU due to the complexity of pharmacotherapy which showed major pDDIs as the most evident (61%) while contraindicated were 1%. Further studies are needed to better explore this area which may help in realizing the goal of good clinical practice and may offer a methodology to further increase drug safety.