The aim of the present study was to evaluate human epididymis protein 4 (HE4) as a marker of epithelial ovarian cancer (EOC) relapse and the combination of this biomarker with contrast-enhanced high-resolution multidetector row computed tomography CE CT imaging to impove the monitoring of EOC patients. Twenty-one patients with advanced EOC (FIGO III/IV) who underwent surgery and adjuvant chemotherapy were retrospectively selected. Each patient contributed 3 serum samples drawn at 3-month intervals: time interval I (1-3 months from surgery), time interval II (4-6 months from surgery) and time interval III (7-10 months from surgery). Serum HE4 and cancer antigen-125 (CA-125) levels were determined by EIA and IRMA assays, respectively. Nine out of the 21 (Group A) women had disease relapse while 12 out of the 21 (Group B) women had stable disease during the follow-up study. Twenty out of the 21 patients underwent at least two CE CT follow-ups with an interval time of ~6 months. One patient did not undergo a second CE CT. In patients with relapsed EOC, an increase in HE4 was noted in 22, 78 and 89% of patients within the time intervals I, II and III, respectively. Positivity for CA-125 was found later at time interval III and only in 44% of patients. Conversely, for EOC patients in remission, increase over the threshold level was observed only for marker CA-125 (4/12). The evaluation of imaging findings at interval time II showed a significant correlation with high levels of HE4 in 6 out of 9 patients with recurrent disease. This study supports the hypothesis that HE4 may serve as an early biomarker for recurrence of EOC. Moreover, HE4 serum levels combined with CE CT imaging may improve the monitoring management of women affected by ovarian cancer.