Human epididymis protein 4 (HE4) has recently been described as a new marker for the early diagnosis of ovarian cancer (OC). The objective of this study was to evaluate (a) the expression of HE4 vs. OC mucin CA125 in 32 patients with OC compared to 163 patients with other malignant or benign pathologies (b) HE4 as indicator of the recurrence of the disease in eight patients followed-up for 20 months after OC diagnosis. Serum HE4 and CA 125 levels were determined by ELISA and IRMA, respectively. At diagnosis, the patients with OC demonstrated high levels of both biomarkers with 96.9% sensitivity for HE4 and 85.7% for CA125. In the other pathologies there was 3.7% positivity for HE4 and 21.0% for CA125. The follow-up study showed an increase of HE4 5-8 months before CA125 increment in five of the eight patients, this early expression being strictly associated to a relapse of the disease. In conclusion, this study showed that HE4, compared to CA125, potentially is a better marker for the diagnosis of OC and could be an important early indicator of the recurrence of the disease.