Objectives: This study aimed to compare the serum endocan levels of patients with uterine fibroids and the healthy control group. Design: A case-control study was designed. Participants/Materials: The study group includes women diagnosed with uterine fibroids, and the control group includes healthy women. Setting: The study was conducted at a tertiary education and research hospital with 130 women (uterine fibroid group, n = 65; control group, n = 65). Methods: Serum endocan levels were determined in the study and control groups using the ELISA method. The number of uterine fibroids was identified, and the volume of uterine fibroids was calculated with ellipsoid formula by ultrasonography. The primary outcome parameter was serum endocan levels in patients with uterine fibroids and healthy control groups. Second, it is aimed to determine the distribution of the serum endocan level of patients according to uterine fibroid number, volume, and clinical presentation. Results: The mean serum endocan level of patient with uterine fibroid was 145.18 ± 169.86 (median: 94.10; Q25–Q75%: 54.50–116.50) pg/mL; it was 88.94 ± 54.21 (median: 76.9; Q25–Q75%: 64.20–152.65) pg/mL in the control group (p = 0.016). According to ROC analysis, cutoff value of the endocan level for uterine fibroid was determined as ≥133.1 pg/mL. For the cutoff value of 133.1 pg/mL, sensitivity was 36.92%, specificity was 89.23%, positive predictive value was 77.40%, and negative predictive value was 58.60%. Above this cutoff value, a 4.8-fold increased significant risk (OR) for uterine fibroid was detected. Limitations: The major limitation of the study is the lack of histopathological examination. Conclusion: Serum endocan levels were found to be higher in women with uterine fibroids compared to the control group, so endocan may be considered as a significant serum marker.