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We studied the effect of flurbiprofen, a non-steroidal anti-inflammatory drug, on muscles that had been subjected to exercise-induced injury. The muscles of the anterior compartment in the limbs of rabbits were cyclically activated as the ankle was simultaneously moved through passive plantar flexion every two seconds for thirty minutes. This treatment imposed acute passive lengthening (eccentric contractions) of the maximally contracted muscles of the anterior compartment. After the eccentric contraction-induced muscle injury, one group of rabbits was treated with oral administration of flurbiprofen, two times a day for six days, while the other group of rabbits served as untreated controls. The contractile, histological, and ultrastructural properties of the muscles were measured before the initial exercise and at three, seven, and twenty-eight days afterward.The group that was treated with flurbiprofen demonstrated a more complete functional recovery than the untreated controls at three and seven days but had a deficit in torque and force generation at twenty-eight days. The administration of flurbiprofen also resulted in a dramatic preservation of the intermediate filament protein desmin. After three days, the proportion of fibers of the extensor digitorum longus that lost desmin-staining was significantly greater in the untreated controls than in the treated animals (34 plus/minus 4.1 compared with 2.9 plus/minus 1.7 per cent) (p < 0.001), a finding that supports the concept of a short-term protective effect. However, the muscles in the treated animals still mounted a dramatic regenerative response, as indicated by the expression of embryonic myosin. Early in the recovery period (at three days), significantly fewer fibers of the extensor digitorum longus (2.2 plus/minus 1.4 per cent) expressed embryonic myosin in the treated animals than in the untreated controls (11.8 plus/minus 1.9 per cent) (p < 0.001). However, at seven days, the expression of embryonic myosin by the muscles from the treated animals (19.5 plus/minus 11.9 per cent) actually exceeded that of the muscles from the untreated controls (16.2 plus/minus 4.1 per cent). This finding suggests either a delayed or an ineffectual regenerative response by the muscles in the treated animals.Non-steroidal anti-inflammatory drugs are used to provide analgesia and sometimes to improve performance after sports-related soft-tissue injuries. This study demonstrates that the effects of flurbiprofen are time-dependent. The contractile properties and histological data suggest that non-steroidal anti-inflammatory drugs cause a short-term gain but a subsequent functional loss. It is not possible to determine if this loss persists or to what extent recovery occurs in the long term. Nonetheless, these results may prompt rethinking of the liberal prescription of non-steroidal anti-inflammatory drugs as treatment for muscle injury.