Purpose <p>Gaucher disease type 1 (GD1) is a multisystem lysosomal disorder in which treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) improves key clinical parameters. However, many patients continue to experience persistent symptoms that are not captured by traditional disease markers. This study evaluated the relationship between pain, fatigue, and health-related quality of life (HRQoL) among treated adults with GD1.</p> Methods <p>In this cross-sectional study, adults with GD1 receiving ERT or SRT (<i>N</i> = 97) completed an online survey including the 36-item Short Form Survey (SF-36), PROMIS^® Fatigue and Pain Interference Short Forms, and the Treatment Satisfaction Questionnaire for Medication©. Associations between demographic factors, treatment variables, symptoms, and HRQoL were assessed using correlation analyses, t-tests, ANOVA, and multiple regression.</p> Results <p>Pain and fatigue were strong, independent predictors of both physical and mental HRQoL, with age additionally predicting physical HRQoL. Significant negative correlations were observed between pain and HRQoL (physical and mental), as well as between fatigue and HRQoL. Participants reported significantly lower HRQoL compared with U.S. population norms across 7 of 8 SF-36 domains.</p> Conclusions <p>Persistent pain and fatigue represent major, under-recognized drivers of impaired quality of life in treated GD1, indicating that current therapies do not fully address the symptomatic burden of disease. These findings support routine integration of validated patient-reported outcome measures into clinical care and highlight the need for adjunctive and mechanism-based approaches to improve patient-centered outcomes.</p>