Cancer-related fatigue and pain after surgery are the most frequent and most incapacitating cancer-related symptoms after breast cancer treatment. Genetic influence of cancer-related fatigue and pain has not been previously investigated. Our aim was to examine the influence of catechol-O-methyltransferase (COMT) Val158Met genotypes on cancer-related fatigue, post-mastectomy pain, and pressure pain hypersensitivity in breast cancer survivors. One-hundred and twenty-eight (n = 128) breast cancer survivors who were treated with radiotherapy and chemotherapy participated in this study. After amplifying Val158Met polymorphisms by polymerase chain reaction, COMT genotype was divided into Val/Val, valine/methionine (Val/Met), or Met/Met. The Piper fatigue scale (PFS) was used to assess cancer-related fatigue. Neck and shoulder/axillary pain intensity was assessed with a numerical pain rate scale (0-10). Finally, pressure pain thresholds (PPT) were assessed bilaterally over the C5-C6 zygapophyseal joints, deltoid muscles, second metacarpal, and tibialis anterior muscles. Breast cancer survivors carrying the Met/Met genotype reported higher levels of fatigue (all subscales, P < 0.001), higher neck pain intensity, and lower PPT over C5-C6 joints and deltoid muscles (all, P < 0.001) relative to those with Val/Met or Val/Val genotypes. The results suggest that breast cancer survivors carrying the Met/Met genotype exhibit higher fatigue, neck pain, and pressure pain hypersensitivity over the neck and shoulder area. This study is important because it strives to understand the factors that predispose some breast cancer survivors to more cancer-related fatigue and increased pain sensitivity.