This study investigated the effects of 10-day lower limb cast immobilization on sarcoplasmic reticulum (SR) Ca2+ regulation. Muscle biopsies were analysed in eight healthy females for maximal rates of SR Ca2+ release, Ca2+ uptake and Ca2+ ATPase activity at control, during immobilization at day 3 (IM 3), day 6 (IM 6) and day 10 (IM 10). Quadriceps muscle cross-sectional area (CSA) and 1-repetition maximum (1RM) leg extension strength were measured to determine the extent of muscle size and strength adaptations. Muscle CSA and strength decreased following 10 days of immobilization (11.8 and 41.6%, respectively, P < 0.01). A decrease in SR Ca2+ uptake rate (analysed per g wet wt) was found at IM 3 (13.2%, P=0.05), with a further decrease at IM 10 (19.8% from control, P < 0.01). At IM 10, a decrease in SR Ca2+ uptake rate (per mg protein) also occurred (19.9%, P < 0.01). Sarcoplasmic reticulum Ca2+ ATPase activity and rate of Ca2+ release were not altered with 10 days of immobilization. This study observed a decrease in SR Ca2+ uptake rate, muscular atrophy and strength loss over 10 days of immobilization in humans.