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Objectives Platinum-resistant ovarian cancer (OC) remains a challenge with few or no treatment options. Methylation of the HOXA9 gene has been found in plasma of patients with OC. It does not, however, occur in blood from healthy individuals. The aim of this study was to evaluate if HOXA9 methylation could predict outcome and identify patients who can benefit from palliative chemotherapy. Methods Plasma from 27 patients with platinum-resistant OC was analyzed by digital PCR with a HOXA9 methylation-specific assay at baseline and before cycle two. The fractional abundance of methylated HOXA9 was calculated and the patients with values increasing above the 95% confidence interval of baseline values was compared with patients having stable or decreasing values. The primary endpoint was progression free survival (PFS). Results At baseline 22 patients (81.5%) had measurable HOXA9 methylation in plasma. Patients (N=4) with a significant increase in HOXA9 methylation after the first cycle had a median PFS of 1.4 months compared to 5.4 months in patients (N=23) with stable or decreasing HOXA9 (p=0.0019). Nine patients were HOXA9 negative before cycle two. The median PFS in this group was 9 months compared to 2.6 months for patients (N=18) with measurable HOXA9 at second cycle (p=0.001) (figure 1). Conclusions The study demonstrated that an increase in HOXA9 methylated DNA could be used as an early marker to predict poor outcome in platinum-resistant OC. Furthermore, absence of HOXA9 methylation was prognostic favorable indicating the potential to identify patients who can benefit from palliative chemotherapy.