The present study examined the skeletal muscle expression of several genes related to the inflammatory process before and after a bout of downhill running. Twenty-nine males between the ages of 18 and 35 years performed a 45-min downhill (-17.5%) treadmill protocol at 60% of maximal oxygen consumption. Venous bloods samples and muscle biopsy samples from the vastus lateralis were donated prior to and at 3-h and 24-h postexercise, along with ratings of perceived muscle soreness. Serum creatine kinase (CK) was determined, as was skeletal muscle gene expression of interleukin (IL)-6, IL-8, IL-12 (p35), tumor necrosis factor-alpha (TNF-α), IL-1β, cyclooxygenase 2 (COX2), and nuclear factor kappa B (NFkB) (p105/p50). Gene expression was analyzed using RT-PCR and compared with a standard housekeeping gene (β-actin). Data were analyzed for statistical differences using multivariate analysis of variance with univariate follow-up. In addition, Pearson correlations were conducted to determine if any significant relationship exists between any of these transcripts and both CK and muscle soreness. Significant (p < 0.05) up-regulations in IL-6, IL-8, and COX2 mRNA expression were observed compared with baseline, whereas no significant changes for IL-12, IL-1b, TNF-α, or NFkB were noted. Significant increases in IL-6 mRNA were observed at 3 h (p < 0.001) and 24 h (p = 0.043), whereas significant increases in IL-8 (p = 0.001) and COX2 (p = 0.046) mRNA were observed at 3-h postexercise. In addition, muscle soreness was significantly correlated with IL-8 at 24 h (r = -0.370; p = 0.048), whereas CK was significantly related to NFkB at baseline (r = -0.460; p = 0.012). These data indicate that increases in the mRNA expression of IL-6, IL-8, and COX2 occur in the vastus lateralis as a result of damaging eccentric exercise in young, recreationally trained males. Further, it appears that IL-8 transcription may play some role in inhibiting postexercise muscle soreness, possibly through regulation of angiogenesis.