Objective: Patients with a BRCA1 or BRCA2 gene mutation have an increased lifetime risk of developing epithelial ovarian cancer (EOC). Screening with CA125 and ultrasound is ineffective for detection of EOC at an early stage and does not reduce the mortality rate of EOC. Therefore, women at risk of developing ovarian cancer are recommended to have risk-reducing salpingo-oophorectomy (RRSO). The benefit of the serum marker human epididymis protein 4 (HE4) in screening programmes is still unknown. Therefore, the authors evaluated serial serum HE4 measurements in patients at high risk of developing EOC based on a familiar or genetic predisposition. Materials and Methods: Patients with BRCA1 or BRCA2 mutation or familiar predisposition that developed EOC during screening were selected from the hospital based cancer registry. HE4 was measured in consecutive serum samples. Results: Cross-linking the hospital-based cancer registry with the serum bank resulted in 182 patients who had developed EOC between 1994 and 2013. More than one serum sample was available of 52 patients but of these only seven patients underwent regular screening. HE4 demonstrated a rapid increase in serum levels just before or at time of diagnosis instead of a longer lead time before diagnosis. This is comparable to the concentrations of serum CA125 in consecutive samples. Conclusion: This is the first study showing that serum HE4 values suddenly increase just before diagnosis and do not precede the development of symptoms. This does not support the use of HE4 with a fixed cut-off value for screening in patients at high risk for EOC.