BACKGROUND: A few days of bed rest or immobilization following injury, disease, or surgery can lead to considerable loss of skeletal muscle mass and strength. It has been speculated that such short, successive periods of muscle disuse may be largely responsible for the age-related loss of muscle mass throughout the lifespan. OBJECTIVE: To assess whether a single intramuscular injection of nandrolone decanoate prior to immobilization can attenuate the loss of muscle mass and strength in vivo in humans. DESIGN, SETTING AND PARTICIPANTS: Thirty healthy (22 ± 1 years) men were subjected to 7 days of one-legged knee immobilization by means of a full leg cast with (NAD, n = 15) or without (CON, n = 15) prior intramuscular nandrolone decanoate injection (200 mg). MEASURES: Before and immediately after immobilization, quadriceps muscle cross-sectional area (CSA) (by means of single-slice computed tomography (CT) scans of the upper leg) and one-legged knee extension strength (one-repetition maximum [1-RM]) were assessed for both legs. Furthermore, muscle biopsies from the immobilized leg were taken before and after immobilization to assess type I and type II muscle fiber cross-sectional area. RESULTS: Quadriceps muscle CSA decreased during immobilization in both CON and NAD (-6 ± 1% and -6 ± 1%, respectively; main effect of time P<0.01), with no differences between the groups (time × treatment interaction, P = 0.59). Leg muscle strength declined following immobilization (-6 ± 2% in CON and -7 ± 3% in NAD; main effect of time, P<0.05), with no differences between groups (time × treatment interaction, P = 0.55). CONCLUSIONS: This is the first study to report that nandrolone decanoate administration does not preserve skeletal muscle mass and strength during a short period of leg immobilization in vivo in humans.