Introduction: In higher immunologic-risk kidney transplant recipients, tacrolimus minimization may reduce nephrotoxicity but risks rejection and dnDSA. Renin-angiotensin system (RAS) blockade may offer anti-inflammatory benefits. We assessed 24-month outcomes of standard- versus low-dose prolonged-release tacrolimus with or without ACEi/ARB. Methods: In this multicenter, prospective, open-label trial, higher-risk de novo kidney transplant recipients were randomized to low- or standard-dose tacrolimus and to ACEi/ARB or other antihypertensive therapy (OAHT). All received basiliximab, mycophenolate, and steroids. Outcomes included survival, BPAR, dnDSA, graft function, proteinuria, protocol biopsies, and safety. Results: 320 patients were randomized; 316 received treatment. At 24 months, patient survival was 98.1% overall. Graft survival was lowest with low-dose tacrolimus+OAHT (91.1%) versus other groups (96.2–98.7%). BPAR was highest with low-dose+OAHT (25.3%) versus others (12.7–16.5%). Class II dnDSA occurred in 13.9% of low-dose+OAHT versus 5.1–7.6% in others. eGFR was similar across groups; proteinuria was lower with ACEi/ARB. Protocol biopsies showed less inflammatory fibrosis progression with low-dose+ACEi/ARB versus low-dose+OAHT. Safety was comparable; ACEi/ARB recipients had slightly lower hemoglobin. Conclusion: In higher immunologic-risk recipients, low-dose tacrolimus with early RAS blockade achieved 24-month outcomes closer to standard-dose regimens than low-dose without RAS blockade. Minimization without RAS blockade increased rejection and dnDSA, supporting further study of risk-stratified minimization with early RAS blockade.