Background: The treatment of patients with advanced cancer generally requires multiple medications, and the consideration of potential drug-drug interactions (DDIs) is important to avoid unintended consequences; therefore, this study assessed potential DDIs in patients treated with oral metastatic castrate-resistant prostate cancer (mCRPC) therapies (abiraterone acetate plus prednisone [AA+P] and enzalutamide [ENZ]). Methods: The MarketScan databases from 03/2012 to 10/2015 were used to conduct a retrospective analysis, in which patients initiated on AA+P or ENZ after 09/2012 (index date) with ≥6 months of continuous eligibility prior to index date and ≥1 PC diagnosis were included. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Weighted Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare the occurrence of potential DDIs. Potential DDI was defined as having a claim for a drug that can interact with the index drug (AA+P or ENZ) during the exposure to index treatment (i.e., the time between the first and last claim [plus days of supply] of the index treatment). Interaction drugs were selected based on the prescribing information for each drug and included strong CYP3A4 inducers and CYP2D6 substrates for AA+P and strong CYP3A4 inducers, CYP2C8 inhibitors, CYP2C9 substrates, CYP3A4 substrates, and CYP2C19 substrates for ENZ. Results: A total of 2,540 AA+P and 1,265 ENZ patients were identified. IPTW resulted in balanced baseline demographic, comorbidities, and disease characteristics. At 3, 6, 9, and 12 months post-index, patients initiated on ENZ were more likely to have a potential DDI during their exposure to ENZ treatment when compared to patients initiated on AA+P (ENZ vs. AA+P, KM rates at 12 months: 30.3% vs. 1.5%, hazard ratio [95% confidence interval]: 28.9 [14.5, 57.4], p < 0.0001). Conclusions: This study showed that mCRPC patients treated with ENZ were more likely to be exposed to a potential DDI during their treatment than those treated with AA+P.