Knee pain can alter lower-extremity neuromechanics and often results in functional disability. The relationship between lower-extremity neuromechanical alterations, due to anterior knee pain, and articular cartilage condition is unclear. The purpose of this study was to determine the independent effect of anterior knee pain during running on articular cartilage condition, as reflected by serum cartilage oligomeric matrix protein concentrations and muscle cocontraction duration. Seven men and five women completed a 30-min run in three different sessions: control (no infusion), sham (isotonic saline infusion), and pain (hypertonic saline infusion). Saline was infused into the right infrapatellar fat pad for the duration of the run. Subject-perceived pain was recorded every 3 min on a 100-mm visual analog scale. During the run, bilateral electromyography was recorded for five leg muscles, and heel and toe markers were used to track foot position. During the 30-min run of the pain session average subject-perceived pain was 27.8 (SD = 2.3 mm) and 19.7 (SD = 1.9) mm greater than during the control (0.0 mm) and sham (8.1 mm) session, respectively (p < 0.01). Knee pain while running did not result in changes in muscular cocontraction duration (p = 0.13). Blood samples were drawn prior to the run, immediately following the run, and 60 min following the run. Samples were analyzed using enzyme-linked immunosortbent assay to determine serum cartilage oligomeric matrix protein concentration. Average serum cartilage oligomeric matrix protein concentration was 14% greater at immediate post run (132.19 ± 158.61 ng/ml; Range = 22.61-290.81 ng/ml) relative to pre run (116.02 ± 118.87 ng/ml; Range = 19.81-234.89 ng/ml) (p < 0.01), and 18% less at 60 min post run (108.45 ± 171.78 ng/ml; Range = 20.84-280.23 ng/ml) relative to immediate post run (Figure 4; p < 0.01). Serum cartilage oligomeric matrix protein did not significantly differ between baseline and 60 min post-exercise (p = 0.29). There was not a difference in cartilage oligomeric matrix protein concentration between sessions. Knee pain while running does not cause an increase in serum cartilage oligomeric matrix protein concentration (p = 0.29). There are two important findings from this study. First, anterior knee pain during a 30 min running session does not appear to independently affect cartilage oligomeric matrix protein concentrations. This implies other factors, aside from anterior knee pain alone, influence articular cartilage degradation during movement that occurs while individuals are experiencing anterior knee pain. Second, the present experimental anterior knee pain model can be used to evaluate the independent effects of anterior knee pain over an extended duration while subjects perform a dynamic activity like running.