Purpose. To determine if the complement system is activated following strenuous eccentrically-biased exercise. Secondly, to determine if complement activation is attenuated (repeated bout effect) following a second bout of the same exercise. Basic procedures. Healthy, active but untrained males performed 2 × 60 min bouts of downhill running, 14 days apart. Samples were taken pre, immediately post (IP), then every hour for twelve hours, and at 24, 48, 72, 96, 120 and 144 h post exercise. Concentrations of C1est, C4, and circulating immune complexes (CIC's) were determined using standardised nephelometery. C6 was determined using radial immunodifusion. The variables were analysed using a repeated measures ANOVA, with significance set at p < 0.05. Main findings. A significant (p < 0.01) run effect was observed for C1est, C4, C6 and CIC's with the concentrations elevated after run 2 compared with run 1. C1est and C4 exhibited significant time effects (p < 0.001). Conclusions. The complement system is activated following a strenuous bout of downhill running. Complement proteins and circulating immune complexes do not exhibit the same traditional ‘repeated bout effect’ as many other common markers of muscle damage/inflammation. The increase in complement proteins following the second bout may indicate enhanced innate immune function and/or an amplification of the immune response to tissue damage through interaction with the adaptive immune system.