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Many studies have reported improved health-related quality of life (HRQoL) from pre- to immediate post-orthotopic liver transplantation (OLT). However, few studies have evaluated longitudinal changes over the first 2 yr post-OLT and none have simultaneously examined objective measures of health-related fitness. A total of 50 OLT recipients (32 males,18 females; 51.4 ± 11.8 yr) completed testing at 2, 6, 12, and 24 months post-OLT. Testing included assessment of exercise capacity (peak VO2), quadriceps muscle strength, body composition, physical activity participation, and self-reported functioning (SF-36). Repeated measures of analysis of variance (ANOVA) with post hoc contrasts was performed to determine differences over time and a second ANOVA assessed differences over time between genders. All patients increased peak VO2, quadriceps muscle strength, and percent body fat (p < 0.0001) from 2 to 24 months. Men and women differed in their changes of peak VO2 and percent body fat (p < 0.05). At 24 months, only 50% of the patients reported participating in regular physical activity. All SF-36 physical measures except general health, improved from 2 to 24 months (p < 0.0001). Measures of health-related fitness and QoL improve over the first 2 yr post-OLT with the greatest gains occurring in the first 6 months and all measures remain lower than recommended for cardiovascular and overall health. A randomized clinical trial of lifestyle modifications such as diet and exercise intervention is warranted to determine the impact of such modifications on HRQoL and fitness post-OLT.