BACKGROUND: Breast cancer treatment has many strategies, each with its own effects on survivors' quality of life (QoL). The current study evaluated factors influencing QoL in women who have undergone mastectomy and compared different treatments based on sociodemographic and clinical factors. METHODS: A retrospective cohort study was conducted utilizing the EORTC Quality of Life breast cancer specific tool and the FACT-B and FBSI questionnaires to measure functional and symptom scales impacting QoL. The questionnaire was administered to 318 Egyptian women post-mastectomy and at 6-month follow-up. Results were reported as median and interquartile range (IQR) or frequency and percentage. Fisher's exact and Kruskal-Wallis tests were used for statistical inferences. Generalized linear models were used to predict QoL measures (outcome) by sociodemographic and clinical variables (independent) with adjusting for potential confounders. Independent variables were selected by elastic net regression. RESULTS: The Global QoL score for this cohort was 42.0 (IQR 25.0-67.0). The functional scale most affected was role (62%), with the cognition having the lowest effect. The most distressing symptoms on the symptom scale were fatigue (65%), insomnia (61%), and pain (60%). FACT-B had a median score of 79.0 (IQR 63.0-95.0). Generalized linear regression indicated that higher cognitive functioning (22.45; p < 0.050) and BCS (6.026, p < 0.010) was positively correlated with women > 60 years old. Urban women correlated with a lower SWB (-2.679, p < 0.05) and higher degree of insomnia. A BMI > 30 correlated negatively with many of the QoL domains. SM or MRM with reconstruction correlated positively with TQOL (8.109 < p < 0.050). Women who received chemotherapy had lower social functioning (-12.41, p < 0.050), BCS (-3.473, p < 0.010), greater association with diarrhoea (8.865, p < 0.010) and financial difficulties (15.23, p < 0.050). In contrast, women who received hormonal therapy had higher role functioning (17.64, p < 0.010), with less complaints of diarrhoea (-10.38, p < 0.010), nausea (-8.668, p < 0.010) and pain (-8.265, p < 0.050). CONCLUSION: These results indicate that sociodemographic and clinical factors affect QoL in Egyptian women post-mastectomy. The worst functioning was the role and emotional scales, and the most distressing on the symptom scale were fatigue, insomnia, and pain making an imperative case for a more multidisciplinary team approach to treatment.