Background: Men with prostate cancer who undergo radical prostatectomy experience a decrease in quality of life, often related to sexual disfunction and urinary incontinence. Knowing and measuring the impact of radical prostatectomy on the individual’s social, emotional, and family quality of life could help to plan and develop an appropriate, patient-centred therapeutic approach. Aim: In this study, we aimed to evaluate changes in quality of life of patients with prostate cancer before and after radical prostatectomy. Methods: A longitudinal, observational study of 114 participants was conducted using the method of test–retest. Quality of life before and after radical prostatectomy was measured through the following self-administered questionnaires: (1) The EORTC QLQ-C30 in its Spanish version was used to assess the generic quality of life the participants; (2) the EORTC QLQ-PR25 in its Spanish version was used to assess the specific, health-related quality of life of prostate cancer patients. Results: A total of 114 men took part in this study. The results from the QLQ-C30 questionnaire indicated an improvement in the dimensions of emotional role and cognitive function, as well as in the symptoms of fatigue, pain, nausea and vomiting, insomnia, and loss of appetite, after surgery. Patients scored lower in the dimensions of role functioning, social function, and economic impact after radical prostatectomy. According to the results from the QLQ-PR25 questionnaire, 61.40% of the participants experienced sexual impotence and 26.31% suffered urinary incontinence after surgery. There were significant differences in some postsurgical outcomes between patients who had neurovascular bundles preserved and those who had not. Conclusions: In-depth knowledge of, and measurement of changes in, quality of life after radical prostatectomy should allow for comprehensive, multidisciplinary, patient-centred care planning. Psychosocial assessment, both before and after surgery, is crucial in patients with prostate cancer. This study was prospectively registered with the CEIC-A on 2012-06-27, with registration number C.P.-C.I. PI12/0088