Background: The choice of prosthesis for mitral valve replacement still remains controversial. This study assessed mortality, bleeding events and reoperation in patients who underwent mitral valve replacement surgery with biological or mechanical substitutes. Methods: A total of 352 patients who underwent mitral valve replacement surgery between 1990 and 2008 with 5 to 23 years of follow-up were retrospectively evaluated in a cohort study. Results: The 5, 10, 15 and 20 year survival rates after surgery using a mechanical substitute were 87.7%, 74.2%, 69.3% and 69.3%, respectively, while after surgery with a biological substitute, they were 87.6%, 71.0%, 64.2% and 56.6%, respectively. There was no significant difference between the two groups (p = 0.38). In the multivariate analysis, the factors associated with death were age, bleeding events and renal failure. The probabilities of remaining free of reoperation at 5, 10, 15 and 20 years after surgery using a mechanical substitute were 94.4%, 92.7%, 92.7% and 92.7%; after surgery with a bioprosthesis, they were 95.9%, 86.4%, 81.2% and 76.5%, respectively (p = 0.073). There was a significantly higher incidence of reoperation for the bioprosthetic valve replacement group (p = 0.008). The probabilities of remaining free of bleeding events at 5, 10, 15 and 20 years after surgery using a mechanical substitute were 95.0%, 91.0%, 89.6% and 89.6%, respectively, while after surgery with a bioprosthesis, they were 96.9%, 94.0%, 94.0% and 94.0%, (p = 0.267). Conclusions: The authors concluded that: 1) mortality during follow-up was statistically similar for both groups; 2) there was a greater tendency to reoperation in the bioprosthesis group; 3) the probability of remaining free from reoperation remained unchanged after 10 years’ follow-up for patients with mechanical substitute valves; 4) the probability of remaining fee from bleeding events remained unchanged after 10 years’ follow-up for patients given bioprostheses; 5) the baseline characteristics of patients were the greatest determinants of later mortality after surgery; 6) the type of prosthesis was not an independent predictive factor of any of the outcomes tested in the multivariate analysis.