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Objective The optimal selection of prosthetic heart valve for dialysis-dependent patients remains controversial. We investigated the comparative effectiveness and safety of mechanical prosthesis (MP) and bioprosthesis (BP) for these patients. Methods After the systematic review, we included studies that involved patients on dialysis undergoing aortic valve replacement or mitral valve replacement (MVR) and reported comparative outcomes of MP and BP. Meta-analysis was performed using random-effects model. We conducted a subgroup analysis based on the valve position and postoperative international normalized ratio (INR), which was extracted from either tables or methods of each study. A meta-regression was used to examine the effects of study-level covariates. Results We included 24 retrospective studies without randomized-controlled trials, involving 10,164 participants (MP = 6934, BP = 3230). Patients undergoing aortic valve replacement with MP exhibited a better long-term survival effectiveness (hazard ratio, 0.64; 95% confidence interval [CI], 0.47-0.86). Conversely, studies including MVR demonstrated little difference in survival (hazard ratio, 0.90; 95% CI, 0.73-1.12). A meta-regression revealed that age had little effect on long-term survival difference between MP and BP (β = –0.0135, P = .433). MP had a significantly greater bleeding risk than did BP when INR was above 2.5 (incidence rate ratio, 10.58; 95% CI, 2.02-55.41). However, when INR was below 2.5, bleeding events were comparable (incidence rate ratio, 1.73; 95% CI, 0.78-3.82). The structural valve deterioration rate was significantly lower in MP (risk ratio, 0.24; 95% CI, 0.14-0.44). Conclusions MP is a reasonable choice for dialysis-dependent patients without additional thromboembolic risk requiring aortic valve replacement, for its better long-term survival, durability, and noninferior bleeding risk compared with BP. Conversely, BP might be an appropriate selection for patients with MVR, given its similar survival rate and lower bleeding risk. Although our meta-regression demonstrates little influence of age on long-term survival difference between MP and BP, further studies stratifying patients based on age cut-off are mandatory.