Ovarian cancer is often diagnosed at advanced stages, when poorly responsive to standard treatment. First-line treatment consists in schemes including cytoreductive surgery followed by adjuvant chemotherapy schemes with platinum and taxane derivatives. Second-line regimens are based on gemcitabine and liposomal doxorubicin. Third line is often not worthwhile because of the high toxicity with poor response to treatment. Previously, we showed that paclitaxel (PTX) carried in non-protein lipid core nanoparticles (LDE) resembling the chemical structure of LDL has remarkably reduced toxicity. Here, the hypothesis was tested whether PTX-LDE could safely benefit patients in third-line treatment setting. Fourteen women unresponsive to second-line chemotherapy for ovarian cancer, aged 61 ± 10 years, clinical stage IV and TqNqM1, were included. PTX-LDE was administered at 175 mg/m, 3/3 week dose. Patients were submitted to clinical examinations before each chemotherapy cycle. Serum biochemistry and imaging examinations to monitor disease progression were performed. In total, 74 cycles of chemotherapy were done and, in all cycles, clinical or laboratorial toxicities were not observed. Median progression-free survival (PFS) was 3.0 months (95% CI 2.0-3.9). In four patients, PFS was >6 months and in 2 > 1 year. The unpreceded, striking absence of toxicity and consistently long PFS, compared to previous results, indicate that at least 4 among 14 patients had tumor arrest by the treatment and clear benefit of PTX-LDE at third-line setting. The absence of observable toxicity allows dose escalating to improve response to treatment, as perspective to be tested in the ensuing studies.