Context: Diagnostic models for endometriosis based on serum biomarkers and patient’s clinical data. Objective: To evaluate the diagnostic potential of preoperative serum levels of CA-125 and HE4 in patients with endometriosis-like symptoms, and to construct diagnostic models with potential clinical applicability. Methods: Preoperative serum levels of CA-125 and HE4 were evaluated using specific electrochemiluminescent assays. Logistic regression was used to construct diagnostic models with optimal diagnostic accuracy based on serum levels of CA-125 and HE4 and clinical data. Patients: In total 221 patients (124 endometriosis patients; 97 control patients) from University Medical Centre Ljubljana, Slovenia and Medical University Vienna, Austria. Interventions: Collection of serum samples and clinical data from women undergoing laparoscopy or laparotomy. Main Outcome Measures: Serum levels of CA-125, body mass index, information on cysts and dyspareunia or dysmenorrhea. Results: CA-125 levels were significantly elevated in endometriosis patients compared to control patients (p = 1.3 ×10-10), while the difference in HE4 levels did not reach significance (p >0.05). The most important confounding variables were body mass index (BMI) and binominal variables, as the presence/ absence of cysts, presence/ absence of dyspareunia, and score for dysmenorrhea. A model with CA-125, BMI, information on cysts and dyspareunia separated patients from controls with sensitivity of 74.0%, specificity of 81.3% and an AUC of 0.836. The second model included CA-125, BMI, information on cysts and dysmenorrhea and had similar diagnostic accuracy with sensitivity of 74.8%, specificity of 79.2% and AUC of 0.819. Conclusions: The constructed models have the potential for noninvasive diagnosis of endometriosis, and might be translated into clinical practice after additional validation.