Objectives Graft failure (GF) is an intractable complication of transplantation, which can severely affect the efficacy of the graft; however, the characteristics, incidence, and risk factors of primary GF have not been well described. This study aimed to analyze the risk factors and outcomes of primary GF to swiftly identify high-risk patients for GF. Methods We performed a case-control study with a case-control ratio of 1:4 with 869 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2015 and December 2019 at our center. Results Nineteen (2.19%) patients experienced primary poor graft function (PGF), while eleven (1.27%) patients developed primary graft rejection (GR). Univariate and multivariate logistic analyses identified two independent risk factors for primary PGF: splenomegaly [P = 0.030; odds ratio (OR), 3.486; 95% confidence interval (CI), 1.139 to 13.109], and donor type [non-matched sibling donor (non-MSD)] (P = 0.018; OR, 4.475; 95% CI, 1.289 to 15.537). However, only donor type (non-MSD) was statistically significant (P = 0.020; OR, 19.432; 95% CI, 1.595 to 236.691) for primary GR. The overall survival was significantly lower in the primary PGF (P = 0.001) and GR group (P = 0.000), respectively, compared to the control group. Conclusion GF can significantly affect the overall survival of patients who underwent allo-HSCT, despite its considerably low incidence. A human leukocyte antigen-matched sibling donor should be the first choice for patients undergoing allo-HSCT for the prevention of GF. Moreover, splenomegaly is an independent risk factor for PGF, and caution must be exercised while treating such patients.