The involvement of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-α) and the sympathetic nervous system in the development of delayed-onset muscle soreness has not been established. I assessed the effect of etanercept, a TNF- α inhibitor, and atenolol, a β1-receptor antagonist, on DOMS induced in the quadriceps muscle. Thirteen male subjects reported to the exercise laboratory on three separate occasions, 6-15 weeks apart. In a randomised, double-blind cross-over format, I administered etanercept (25mg), atenolol (25mg) or placebo, one hour before the exercise. Subjects then completed four sets of 15 repetitions at 80% of their one repetition maximum (1RM) on a 45° inclined leg press machine. Muscle strength changes were detected by remeasuring the subject’s 1RM 24h, 48h and 72h after the exercise. Sensitivity to pressure of the quadriceps muscle was measured using a pressure algometer before and 24h, 48h and 72h after exercise. The subject’s perception of the pain was measured with the visual analogue scale and McGill Pain Questionnaire. Muscle tumour necrosis factor-alpha concentration was measured before exercise and then 2h and 24h after exercise in four subjects. Muscle strength was impaired 24h and 48h after exercise regardless of agent administered (P < 0.001). At 72h after exercise, muscle strength was significantly improved (P < 0.01) in subjects receiving etanercept and atenolol compared to those receiving placebo. The subject’s were significantly more sensitive to pressure applied to the quadriceps 24h, 48h and 72h after exercise compared to before exercise, regardless of agent administered (P < 0.001). The VAS was elevated significantly at all three time intervals, with no difference after etanercept or atenolol administration compared to that of placebo. There was no significant difference in the muscle TNF-α concentration between any of the time intervals or between subjects receiving placebo and etanercept (P=0.065). The administration of atenolol and etanercept, at the regimen used, had no effect on the soreness associated with DOMS.