Diseases involving chronic inflammation can lead to prolonged exposure of skeletal muscle to inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha), which may contribute to the skeletal muscle weakness seen in these conditions. In this study we examined the effect of a prolonged exposure to TNF alpha on intracellular Ca2+ transients elicited in skeletal C2C12 myotubes. A 48-h exposure to TNF alpha (10 ng/mL) significantly reduced the peaks, time to peak, and rate of Ca2+ decay of electrically induced Ca2+ transients elicited in C2C12 skeletal myotubes. TNF alpha exposure had no significant effect on the resting Ca2+ levels. The results of this study indicate that prolonged exposure to TNF alpha decreases sarcoplasmic reticulum Ca2+ release in cultured skeletal muscle cells. This altered Ca2+ release could contribute to the muscle weakness found in conditions involving chronic inflammation.