To determine the effects of etanercept (anti-TNF-alpha) on surgically induced endometriosis in a rat model. This is a prospective, randomized, controlled, experimental study that was carried out at the Experimental Research Center of Yeditepe University (YUDETAM). Thirty female nonpregnant, nulligravid Wistar-Hannover albino rats were used. The summary of the technique: surgical induction of endometriosis, administration of estrogen for 2 weeks, and laparotomy; administration of etanercept for 2 weeks following the induction of endometriosis and laparotomy; administration of estrogen for 2 weeks and necropsy. The volume and histopathological scores of the endometriotic foci were evaluated. One-hundred twenty uterine horns were implanted in 30 rats. Endometriosis was completely formatted in 112 lesions (93.3%). No rats were lost. In the etanercept group, the lesions' volumes were 83.9 +/- A 13.1, 47.2 +/- A 8.4, and 96.7 +/- A 34.8 mm(3) at the end of the second week (pretreatment stage), at the end of the fourth week (post-treatment stage), and at the end of the sixth week, respectively (P = 0.007). Histopathologic scores were 2.3 +/- A 0.2, 1.7 +/- A 0.2, and 1.9 +/- A 0.1, respectively (P = 0.08). The changes in the other groups were not statistically significant. Etanercept, a fusion protein consisting of human recombinant soluble TNF receptor-2, neutralizes TNF activity. Anti-TNF therapy could be a new non-hormonal therapeutic option for the treatment of endometriosis in humans.