Inflammation response in exercise of healthy humans is significantly different than that which is commonly reported for chronic inflammatory conditions. Regardless of the scenario, cytokines such as Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-1b have demonstrated pro-inflammatory functions, while IL-6 has demonstrated versatile pro- and anti-inflammatory roles when exercise is a factor. Prolonged skeletal muscle contractions of sufficient intensity have been shown to induce significant muscle protein damage and a complex inflammatory cascade involving IL-6 and, separately, Heat Shock Proteins (HSP), and components of the Mitogen-Activated Protein Kinase (MAPK) pathway. This cascade not completely understood in any scenario, particularly in humans. Thus the role of inflammation in regards to exercise, particularly resistance training, has not been elucidated. To determine the effects of concentric (CON) and eccentric (ECC) contractions on creatine kinase (CK), lactate dehydrogenase (LDH), and IL-6 signaling in regards to IL-1b, TNF-α, HSP-72, Nuclear Factor-kappa B (NF-?B), p38 MAPK, Signal Transducer and Activator of Transcription (STAT)-1 and STAT-3 and the potential cytoprotection HSP-27. Six active males (19.33 ± 1.03 yrs; 181.94 ± 6.40 cm; 72.83 ± 12.78 kg) participated in two separate bouts of 10 × 10 unilateral isokinetic knee extensions at 30°/sec. Each bout consisted of either CON or ECC contractions on either the right or left leg; each contraction type and leg was utilized once for each subject. Isokinetic strength tests were performed five days pre- and 24 and 48 hours post-exercise. Serum CK, LDH, IL-6, IL-1b, and TNF-α were assessed immediately preexercise (PRE), immediately post-exercise (PX), and at 2, 6, 24, and 48 hr PX. IL-6, HSP-27, and HSP-72, NF-?B, p38 MAPK, STAT-1 and STAT-3 protein and mRNA expression of IL-6, HSP-27, and HSP-72 were assessed from vastus lateralis biopsies (Bergstrom ) collected at PRE, PX, and 2 and 6 hr PX. Repeated measures MANOVAs and subsequent univariate analyses were performed on all data. Peak torque decreased (p < 0.05) at 24 and 48 hr PX. CK, but not LDH, increased (p < 0.05) similarly following CON and ECC. Serum cytokines were different (p < 0.05) between CON and ECC, but did not change over time. In muscle, NF-?B (p < 0.05) increased and STAT-1 decreased (p < 0.05). ECC contractions demonstrated significantly greater expression for IL-6, p38 MAPK, and STAT-3 than did CON, with a trend (p = 0.093) for STAT-1. There was significant CON/ECC interaction among NF-?B and STAT-1 and a trend (p = 0.074) for HSP-72. Skeletal muscle mRNA expression demonstrated no significant results. Both CON and ECC bouts demonstrated muscle damage and fatigue, but were not sufficient to induce a systemic inflammatory response. Intramuscular inflammatory response was most robust for NF-?B and STAT-1. The hypothesis of ECC stimulating the IL-6 pathway more so than CON is supported the relationship in expression of IL-6, p38 MAPK, STAT-1 and STAT-3. This is novel evidence of a relationship among these factors. Bouts of resistance exercise that include ECC contractions can favorably affect the exercise inflammation response; perhaps more so than lower intensity CON-only contractions.