Purpose of investigation: By the comparison between most used tumor marker trend (cancer antigen 125: CA 125 and human epididymal secretory protein E4: HE4) before and after laparoscopic surgery, the aim of the present study was to assess HE4 usefulness in ovarian benign cyst and endometrioma diagnosis. Materials and Methods: Thirty-eight patients were enrolled in this prospective study: 25 women underwent unilateral endometriosis ovarian cyst excision, 13 underwent benign ovarian cyst incision, and 26 were healthy controls. CA 125 and HE4 serum levels were estimated before surgery (in the early proliferative phase of the cycle) and one month after surgery. Results: A statistically significant decrease of CA 125 serum level was found after an endometrioma surgical excision but no decreases in HE4 serum level. Conclusion: In patients with endometrioma, no alteration was found in HE4 serum levels before and after surgery, while CA125 serum levels decreased after surgery. HE4 may better distinguish a malign cyst from benign one, but it is not useful in the diagnosis of low risk endometrioma.