Context: We recently demonstrated that 28 days of bedrest in healthy volunteers results in a moderate loss of lean leg mass and strength. Objective: To quantify changes in muscle protein kinetics, body composition and strength during a clinical bedrest model reflecting both physical inactivity and the hormonal stress response to injury or illness. Design: Muscle protein kinetics were calculated during a primed, continuous infusion (0.08 µmol•kg^-1•min^-1) of ¹³C₆ - phenylalanine on Day 1 and 28 of bedrest. Setting: The General Clinical Research Center at the University of Texas Medical Branch. Participants: Healthy male volunteers (n = 6; 28 ± 2 y; 84 ± 4 kg; 178 ± 3 cm). Intervention: During bedrest, hydrocortisone sodium succinate was administered intravenously (Day 1 and 28) and orally (Days 2-27) to reproduce plasma cortisol concentrations consistent with trauma or illness (22 µg/dL). Main outcome measures: We hypothesized that inactivity and hypercortisolemia would reduce lean muscle mass, leg extension strength and muscle protein synthesis. Results: Volunteers experienced a 28.4 ± 4.4% loss of leg extension strength (P = 0.012) and a 3-fold greater loss of lean leg mass (1.4 ± 0.1 kg), (P = 0.004) compared with our previous bedrest-only model. Net protein catabolism was primarily due to a reduction in muscle protein synthesis (FSR: 0.081 ± 0.004 (Day 1) vs. 0.054 ± 0.007%/h (Day 28), P = 0.023). There was no change in muscle protein breakdown. Conclusion: Prolonged inactivity and hypercortisolemia represents a persistent catabolic stimulus that exacerbates strength and lean muscle loss via a chronic reduction in muscle protein synthesis.