Of all the neoplastic sites, colorectal cancer (CRC) is one of the most common cancers in the family. Studies estimate that approximately 30% of all the CRC cases are a hereditary form of the disease with a potentially high impact on the quality of life (QoL), with a high risk of recurrence, and with bio–psycho–social functioning. The aim of the study was to assess the QoL of colorectal cancer patients with genetic risk by using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire version QLQ-CR29. Materials and methods: The cross-sectional, single-center study was performed on a group of 32 patients with genetic risk of colorectal cancer, who underwent preoperative chemoradiation and surgery. Results: The series of values for the scores on the symptom scale varied between 15 and 30, and the average level of symptom scores did not differ significantly between gender (22.0 vs. 22.75; p = 0.636), highlighting a moderate impairment of QoL. Scores for the emotional functioning scale were significantly lower in men (10.33 vs. 13.25; p = 0.049), as were the scores for the physical functions (15.67 vs. 19.15; p = 0.039), showing a decrease in QoL. Conclusions: The overall score showed an average QoL in patients with colorectal cancer with genetic risk, highlighting significant differences in psycho-emotional functioning between women and men.