Background Saturated fatty acid esters may cause mastalgia via hypersensitivity of breast epithelium to circulating hormones. Evening primrose oil (EPO) may restore the saturated/unsaturated fatty acid balance and decrease sensitivity to steroidal hormones or prolactin. Conflicting results exist regarding EPO treatment for mastalgia. The aim of this study was to determine the effectiveness of EPO and factors affecting its efficacy in treatment of mastalgia. Methods The study included 1015 patients, ages 14-82 (mean age 42.21 +/- 10.8), admitted to Acibadem Breast Clinic between January 2015 and March 2018. The patients were divided into group I (n = 581) treated with EPO (1300 mg, twice a day) and group II (n = 434) treated with paracetamol (500 mg, twice a day). The visual analog scale was used to assess EPO's therapeutic efficacy, compared with paracetamol, measured at admittance, 2 weeks, and 6 weeks. Clinical factors affecting the efficacy of EPO were analyzed. Results The therapeutic efficacy of EPO on mastalgia was significantly higher than with paracetamol (p < 0.001). Factors significantly affecting the efficacy of EPO treatment were hormone replacement therapy (HRT), IUD-with-levonorgestrel, iron deficiency, overt hypothyroidism, and Hashimoto thyroiditis (p < 0.01). Replacement of iron or thyroid hormone efficiently treated mastalgia in patients that did not respond to EPO treatment. Side effects (allergy, anxiety, blurred vision, constipation, and nausea) were rare and not statistically significant (p = 0.88). Conclusion EPO can be used in the treatment of mastalgia without significant side effects. HRT, IUD-with-levonorgestrel, iron deficiency, overt hypothyroidism, and Hashimoto thyroiditis significantly affect the efficacy of EPO on mastalgia.