Increasing extracellular K+ concentration ([K+](o)) from 4 to 7-14 mM reduced both tetanic force and resting membrane potential (E(m)) in isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles of the mouse. The tetanic force-[K+](o) relation-ships showed a greater force loss over 8-11 mM [K+](o) in soleus than EDL, mainly because the E(m) was 2- 3 mV less negative at each [K+](o) in soleus. The tetanic force-resting E(m) relationships show that force was reduced in two phases: phase 1 (E(m) < -60 mV), a 20% force decline in which the relationships superimposed in soleus and EDL, and phase 2 (E(m) -60 to -55 mV), a marked force decline that was steeper in EDL than soleus. Additionally in phase 2, longer stimulation pulses restored tetanic force; the twitch force-stimulation strength relationship was shifted toward higher voltages; caffeine, a myoplasmic Ca2+ concentration elevator, increased maximum force; and twitch force fell abruptly. We suggest that 1) the K+-depressed force is due to reduced Ca2+ release resulting from an altered action potential profile (phase 1) and inexcitable fibers due to an increased action potential threshold (phase 2), and 2) K+ contributes to fatigue in both fast- and slow-twitch muscle when it causes depolarization to about -60 mV.