Many physical activities can induce both transient and long-lasting muscle dysfunction. The separate and interactive effects of short-term fatigue and long-lasting contraction-induced damage were evaluated in an in vitro mouse soleus preparation (35°C) using the work loop technique. Repetitive fatiguing work loops reduced positive work (work produced by the muscle), increased negative work (work required to reextend the muscle), and reduced cyclical power (net work/time) immediately after treatment. These changes were readily reversible. The fatigue treatment had no long-term effects on optimal muscle length (L_o) and isometric force (P_o). High strain lengthening work loops, where the muscle contracted eccentrically, resulted in both immediate and long-lasting positive work, power, and P_o deficits as well as a shift in L_o to longer lengths. When the treatments were combined, i.e., fatigued muscles subjected to eccentric activity, the immediate power deficit exceeded the sum of the power deficits noted for the other two treatments. Much of this effect was due to an exaggerated rise in negative work. However, in the long term, power and P_o deficits and the shift in L_o were reduced compared with the damage-only treatment. These results show that 1) the immediate effects of combined fatigue and damage on cyclical power are synergistic, in large part because of a reduced ability of the muscle to relax; and 2) fatigued muscles are less susceptible to long-term contraction-induced dysfunction. Fatigue may protect against long-term damage by reducing the probability that sarcomeres are lengthened beyond myofilament overlap.