OBJECTIVES: Type-1 Gaucher Disease (GD1) causes anemia, thrombocytopenia, hepatosplenomegaly, and skeletal pathology. Patients’ health-related quality of life (HRQoL) has been shown to be significantly diminished relative to the U.S. general population. Velaglucerase alfa is an enzyme replacement therapy (ERT) with the most comprehensive clinical trial registration program for an approved ERT in GD1 and has been reported as an effective and well-tolerated therapy. METHODS: The change in HRQoL, measured using the Short-Form-36 version 2 (SF-36 v2) in adults at baseline and 1 year in a randomized, double-blinded, parallel-group, two-dose Phase III clinical trial of velaglucerase alfa, was designated a priori a non-key secondary endpoint.  RESULTS: The mean baseline (SD) was 42.3 (8.00) and 46.0 (5.90) for the norm-based Physical Component Summary (PCS) and 41.7 (12.6) and 48.1 (10.7) for the norm-based Mental Component Summary (MCS), respectively, for the 45 U/kg (N=8) and 60 U/kg (N=7) treatment arms; the mean U.S. normal population score = 50; 1 SD = 10). Fourteen adult GD1 patients had completed both a baseline and 1 year SF-36 HRQoL assessment (N=8 receiving 45 U/kg; N=6 receiving 60 U/kg).  The respective mean change at 1 year [95% CI] for the PCS and MCS was 4.2 [-4.6, 13.0] and 4.1 [1.0, 7.2] at the low dose and 1.7 [-3.9, 7.2] and 1.2 [-7.9, 10.3] at the high dose.  Non-significant increases were observed in nearly all of the 8 individual SF-36 v2 health domains compared to baseline, however, the mean increases, as well as the mean increases in the norm-based PCS and MCS summary measures, were aligned with the expected achievements of therapeutic goals for HRQoL.  CONCLUSIONS: In addition to clinical efficacy and safety, velaglucerase alfa showed clinically important increases in HRQoL in adults as measured by the SF-36 v2 within 1 year, however, further studies are needed.