Objectives: To test the hypothesis that c-Jun NH2-terminal Kinases (JNKs) inhibitors can reduce endometriosis in a baboon model with induced endometriosis. Design: Prospective randomized, placebo-controlled study in nonhuman primates Methodology: Laparoscopic induction of endometriosis was performed in 20 baboons using intrapelvic seeding of menstrual endometrium inside the pelvic cavity. Fifty days after induction, a pretreatment videolaparoscopy (baseline disease assessment) was performed. The type, surface area and volume of endometriotic lesions (typical, red, white, or suspicious) were recorded and the revised American Society for Reproductive Medicine score and stage were calculated. All 20 baboons were then randomized into 4 groups and treated for a total duration of 60 days. They received banana (placebo, n=5), 20 mg/kg JNK inhibitor orally (n=5), JNK Inhibitor + 10mg Medroxy progesterone acetate (MPA) orally (n=5), Cetrorelix acetate (GnRH antagonist) 3 mg per baboon every three days, subcutaneously (n=5). A posttreatment videolaparoscopy was performed 60 days after the start of medical treatment to compare the extent of endometriosis in the 4 groups. Data were analysed with nonparametric statistics. Results: In contrast with the placebo group, baboons treated with JNK Inhibitor, with JNK Inhibitor + MPA, or with Cetrorelix all showed a statistically significant reduction of the total surface area (p=0.03, 0.02,0.02) and volume (p=0.01,0.01,0.01) of endometriotic lesions after treatment when compared to their pelvic status before treatment. These data were confirmed when red lesions were analyzed separately. Remodelling of red active lesions into white lesions was observed more frequently (p=<0.05) in baboons treated with the combination of JNK inhibitor and MPA than in baboons treated with placebo. Conclusion: JNK inhibitors effectively diminish the burden of endometriosis disease in a baboon model with induced endometriosis. The addition of MPA to JNK inhibitors may favor the healing process of endometriotic lesions. Support: Istituto di Ricerche Biomediche “A. Marxer” RBM S.p.A,Turin, Italy.