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Nonsteroidal anti-inflammatory drugs (NSAID) are frequently used in sports medicine but few studies have documented their potential importance in modifying exercise-induced changes in renal function. The effects of indomethacin (50 mg orally every 8 h for 36 h) on renal blood now (RBF) and glomerular filtration rate (GFR) were investigated in eight fit healthy males (age 21–42) before and after 30-min treadmill exercise at 80% O2max and during 120-min recovery. Each volunteer served as their own control. There were no differences between control and indomethacin for the resting values of RBF, GFR, or renal vascular resistance (RVR). Using analysis of variance for repeated measures, indomethacin produced a significant reduction in RBF compared with control (P = 0.009) that was associated with a significant elevation in RVR (P = 0.027). Changes in GFR mirrored the changes in RBF but differences failed to reach statistical significance. These results suggest that with sustained exercise indomethacin can compromise renal function and potentiate the risk of developing acute renal failure. Indomethacin and other NSAID are widely used in the sports arena, and athletes should be warned of the potential danger of their use when renal function may be compromised.