Background <p>This study aims to measure the health-related quality of life (HRQoL) impact of rare diseases (RDs) and eye diseases, chronic diseases, Helicobacter pylori infection, and to assess their disease burden in China.</p> Methods <p>A national online survey was conducted among 21,909 Chinese residents between June 20 and August 31, 2022. The four self-reported medical conditions were identified. HRQoL was measured using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L). Both the multiple linear and logistic regression models were adopted to assess their impacts on EQ-5D utility and VAS scores. The prevalence-based quality-adjusted life-year (QALY) loss was calculated for RDs and other medical conditions. For each condition, QALY loss was calculated for 100,000 persons in 1 year using the associated reduction in EQ-5D utility score estimated in regression analysis.</p> Results <p>The self-reported prevalence of RDs was 1.2%, and the prevalence of eye diseases, chronic diseases, and Helicobacter pylori infection (unsure and yes) was 46.6%, 25.9%, 25.1% and 3.8%, respectively. All conditions, except for unsure Helicobacter pylori infection, were associated with significantly reduced EQ-5D utility scores, and RDs had the most profound impact on the utility score (β = -0.117; 95% confidence interval (CI): -0.151,-0.083). Chronic disease had the largest annual QALY loss per 100,000 persons at -1036.0 (95% CI: -1139.6, -906.5), followed by eye diseases at -279.6 (95% CI: -466.0, -139.8), RDs at -140.4 (95% CI: -181.2, -99.6), Helicobacter pylori infection (yes) at -98.8 (95% CI: -140.6, -57.0), and Helicobacter pylori infection (unsure) at -75.3 (95% CI: -157.7, 25.1).</p> Conclusion <p>RDs have severe impact on HRQOL among Chinese residents, leading to the disproportionate QALY loss at population-level compared to their low prevalence. Therefore, greater attention should be paid to RDs and effective treatment strategies need to be developed.</p>