Postoperative nausea and vomiting (PONV) is prevalent in surgical patients with known risk factors: general anesthesia, female, nonsmoker, motion sickness history, and PONV history. Common treatment involves ondansetron; however, the effects are short-lived, and supplemental medication may be required. Meclizine, a long-acting drug with a low side-effect profile, may be ideal in combination with ondansetron for at-risk patients. We randomized 77 subjects scheduled for general anesthesia and screened for 4 of 5 PONV risk factors for experimental or control group assignment. Severity of PONV was measured using a 0 to 10 verbal numeric rating scale (VNRS). Other measured variables included time to onset and incidence of PONV and total antiemetic requirements. No significant differences in demographics (excluding weight), surgical or anesthesia time, analgesic requirements, or nausea incidence in the postanesthesia care unit (PACU) and same-day surgery unit were noted. The meclizine group had lower VNRS scores in the PACU at 15 (P = .013) and 45 (P = .006) minutes following rescue treatment. The incidence of nausea was lower in the meclizine vs. placebo group (10% vs. 29%) following discharge (P = .038). Prophylactic meclizine resulted in lower incidence and severity of PONV in a high-risk population, especially after rescue treatment.