We retrospectively compared the efficacy and health-related quality of life (HRQoL) of (1) first-line haploidentical hematopoietic stem cell transplantation (haplo-HSCT, n = 146) combined with unrelated cord blood (UCB) infusion and (2) first-line immunosuppressive therapy (IST, n = 219) in acquired severe aplastic anemia (SAA) patients. At 6 months post treatment, 90.30% patients in the haplo-HSCT group and 18.78% patients in the IST group achieved normal blood routine (P < 0.0001). The time required to discontinue red blood cells and platelets transfusion in the IST group were longer than in the haplo-HSCT group (P < 0.0001). The estimated overall survival at 4 years was similar (80.1 ± 3.5% vs. 80.1 ± 3.0%, P = 0.726); the estimated failure-free survival (FFS) at 4 years was 77.8 ± 3.7% in the haplo-HSCT group and 48.0 ± 3.6% in the IST group (P < 0.0001). Patients treated with haplo-HSCT scored significantly better in the HRQoL than treated with IST (P < 0.0001). In the multivariate analysis, first-line haplo-HSCT was the favorable factor for FFS and HRQoL (P < 0.0001). These results suggest that first-line haplo-HSCT combined with UCB infusion might provide a better chance of success and HRQoL than first-line IST for SAA patients.