Background: Thrombocytopenia is a complication after liver transplantation. This study’s aims were to evaluate the role of CYP3A5 genotypes on tacrolimus-induced thrombocytopenia after orthotopic liver transplantation. Methods: In this retrospective case–control study, data from 100 patients who underwent deceased-donor liver transplantation (DDLT) were divided into CYP3A5*3 genotype (donor/recipient) tacrolimus fast- (A*/A*, n = 22), intermediate- (A*/GG, n = 20; GG/A*, n = 31) and slow-metabolizer (GG/GG, n = 27) groups. Platelet count changes and prognosis for 180 days after surgery were compared. Results: Platelet counts declined significantly after DDLT, especially on postoperative day (POD) 3, and continued at low levels for a week thereafter in all groups. In the GG/GG group, platelet counts on POD3 (50.29 ± 5.44 × 109/L) were the lowest among the groups (A*/A*, 71.00 ± 6.22 × 109/L; A*/GG, 57.95 ± 6.21 × 109/L; GG/A*, 75.90 ± 5.56 × 109/L) (p = 0.006). Compared with the A*/A* genotype, tacrolimus nadir levels were significantly higher in GG/GG genotype patients, who also exhibited a higher incidence of hemorrhage (22.2%, p = 0.011). A combination of a nadir blood concentration of tacrolimus ≥ 4.74 ng/mL and spleen size ≥ 165.5 mm was a risk factor for increased thrombocytopenia after DDLT on POD3, with an AUC of 0.735 (sensitivity, 77.2%; specificity, 41.7%). Conclusions: A high blood concentration of tacrolimus after the early stage of DDLT is a major risk factor for hemorrhage. For the CYP3A5 genotype (GG/GG), controlling the blood concentration of tacrolimus below the target concentration until POD3 can avoid thrombocytopenia-related complications.