BACKGROUND: Pharmacotherapy prophylaxis embedded in Enhanced Recovery After Surgery (ERAS®) protocols is largely unknown because data related to agent choice, dosing, timing, and duration of treatment currently are not collected in the ERAS Interactive Audit System (EIAS®). This exploratory retrospective randomized cohort study characterized pharmacologic regimens pertaining to prophylaxis of surgical site infections (SSI), venous thromboembolism (VTE), and post-operative nausea and vomiting (PONV). MATERIALS AND METHODS: The records of 250 randomly-selected adult patients that underwent elective colorectal (CR) and gynecologic/oncology procedures (GO) at an ERAS® site in North America were abstracted using REDCap. In addition to descriptive statistics, bivariate associations between categorical variables were compared. RESULTS: Rates of SSI, VTE, & PONV were 3.3%, 1.1%, and 53.6%, respectively. Mean length of stay (LOS) for CR was 6.9 days and for GO, 3.5 days (p < 0.001). The most common antibiotic prophylaxis was one-time combination cefazolin 2 g and metronidazole 500 mg between 16 and 30 min preoperatively after chlorhexidine skin preparation. The most frequent VTE prophylaxis was tinzaparin 4500 units SC daily continued for at least 7 days after hospital discharge in oncology patients. PONV was related to longer LOS in both groups. Total morphine milligram equivalents (MME) was positively related to PONV and LOS in both CR & GO groups. CONCLUSION: Guideline-consistent pharmacologic prophylaxis for SSI and VTE for both CR and GO patients was associated with low complication, LOS, and readmission rates. LOS in both groups was highly influenced by total MME, incidence of PONV and multi-modal anesthesia.