Background <p>Domino kidney paired donation and Two-Way Paired Exchange have emerged as vital strategies to expand the donor pool in renal transplantation, especially for patients facing ABO or HLA incompatibilities. Despite their potential benefits, concerns remain regarding immunological risks, infectious complications, and long-term graft survival.</p> Methods <p>In this retrospective cohort study conducted at Medicana Transplant Center, 980 adult kidney transplant recipients were categorized into three groups: Domino (<i>n</i> = 144), Two-Way Paired Exchange (<i>n</i> = 350), and Normal Transplant (<i>n</i> = 486). Baseline characteristics, acute rejection rates, and surgical or infectious complications were collected, alongside data on 1-year and 5-year patient and graft survival. Statistical analysis included Kaplan-Meier survival curves and Cox proportional hazards modeling for independent predictors of graft outcomes.</p> Results <p>The Domino group had the highest 1-year acute rejection rate (17.4%) compared to Two-Way Paired Exchange (4.3%) and Normal Transplant (3.7%), yet 1-year graft survival rates remained comparable (92%, 95%, and 96%, respectively; <i>p</i> = 0.271). Infectious complications were more frequent in the Domino group (25%) than in others (<i>p</i> &lt; 0.01). Extended follow-up to 5 years indicated no statistically significant difference in overall graft or patient survival among the three groups (log-rank <i>p</i> = 0.197), despite a trend toward lower 5-year graft survival in the Domino group. Donor-specific antibodies and higher HLA mismatches independently predicted acute rejection.</p> Conclusions <p>Domino transplantation, while associated with higher immunologic challenges, achieves acceptable short-term and 5-year outcomes akin to Two-Way Paired Exchange and Normal Transplant. Careful immunosuppressive strategies, vigilant monitoring, and collaborative protocols are integral for optimizing long-term success in high-risk transplant scenarios.</p>