Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver disease of various etiologies. Its use, however, remains limited due to the scarcity of donor organs. Measures to assess health-related quality of life (HRQOL) are increasingly being implemented to examine the efficacy of medical therapies involving scarce resources. HRQOL was assessed and compared between 88 male and 61 female patients before and after liver transplantation. Data were gathered from subjects having completed a questionnaire pre-OLT, and again at 1 year and 2 years post-OLT. This questionnaire, developed specifically for OLT patients, contains at its core questions derived from several well-established instruments measuring health status and HRQOL. Male OLT recipients reported a higher degree of overall HRQOL than that reported by female OLT recipients, both before and after OLT. When controlling for disparity in education between the sexes, findings revealed that among the lesser educated (≤12 years), men and women scored similarly, while among the more educated (>12 years), men scored higher than women. Employment findings revealed a higher percentage of men working before transplant and at 1-year post-OLT when compared with women. At 2 years post-OLT, men and women exhibited similar employment rates. Male OLT recipients report a higher level of overall HRQOL than that reported by female OLT recipients, both before and after liver transplantation. Education appears to significantly affect HRQOL and may account for, at least in part, differences in reported HRQOL between male and female OLT recipient.