A side effect of lithium (Li+) treatment is fatigue. Li+ decreases inositol triphosphate (IP3) accumulation and IP3 may play a role in excitation-contraction (E-C) coupling in skeletal muscle. Li+ carbonate (600 mg b.i.d. x 6 days) was administered in a randomized, double-blind fashion to 12 males to measure the effect upon muscle contractile function: peak twitch torque (PTT), time to PTT, half-relaxation time, maximal voluntary contraction strength (MVC), percent motor unit activation, M-wave characteristics, and tetanic torque (3 min at 15 and 50 Hz). Li+ resulted in a significant decrease in 15- and 50Hz tetanic torque (P<0.00l), MVC, and resting PTT (P<0.05). There were no effects of Li+ upon any of the other measured variables. Li+ had a negative effect upon E-C coupling and did not affect central motor unit recruitment. Elucidation of the role of IP3 in E-C coupling may help to understand fatigue in some neuromuscular disorders.