Background: Axonal sensoryperipheral neuropathy is the major dose-limiting side effect of paclitaxel. Omega-3 fatty acids have beneficial effects on neurological disorders from their effects on neurons cells and inhibition of the formation of proinflammatory cytokines involved in peripheral neuropathy. Methods: This study was a randomized double blind placebo controlled trial to investigate the efficacy of omega-3 fatty acids in reducing the incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN). Fifty seven eligible patients with node positive breast cancer were randomly assigned to take omega-3 fatty acid soft gel capsules, 640 mg t.i.d during chemotherapy with paclitaxel for 12 weeks or sun flower soft gel capsules as placebo. Incidence and severity of PIPN, serum level of inflammatory markers: IL-1 beta, IL- 6, TNF-alpha and HsCRP, as well as concentrations of EPA and DHA in the serum phospholipids of the patients, were assessed before the onset of chemotherapy and after the cessation of therapy. Results: Twenty one patients (70%) of the group taking omega-3 fatty acid supplement did not develop PN while it was 40.7 %( 11 patients) in the placebo group. A significant difference was seen in PN incidence (OR=0.3, .95% CI= (0.10-0.88), p=0.029), but there was not a statistically significant difference of PIPN severity between the two study groups. The serum levels of aforementioned inflammatory markers were not statistically different between the active group and the control group but, a considerable difference was observed according to the serum concentrations of EPA and DHA after the end of the supplementation period (P<0.001). Conclusions: Omega-3 fatty acids may be an efficient neuroprotective supplement for prophylaxis against PIPN. They were able to reduce the incidence of PIPN in these study patients. Patients with breast cancer have a longer disease free survival rate with the aid of therapeutical agents. Finding a way to solve the disabling effects of PIPN would significantly improve the quality of life of these cancer patients. Clinical trial information: NCT01049295.