The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (−15; 95% CI −24.1 to −5.8; P = 0.002), social functioning (−15.3; 95% CI −25.5 to −5.1; P = 0.004), role physical (−28.4; 95% CI −43.1 to −13.7; P < 0.001), role emotional (−23.9; 95% CI −40.1 to −7.7; P = 0.004), and mental health scales (−11.3; 95% CI −21.2 to −1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol. 91:995–1001, 2016. © 2016 Wiley Periodicals, Inc.