BACKGROUND: Up to 30% of individuals infected with COVID-19 experience persistent symptoms, known as post-COVID-19 condition (PCC), which can impair health-related quality of life (HRQoL). While post-COVID-19 condition (PCC) is known to affect health-related quality of life (HRQoL), the specific contribution of individual symptoms remains underexplored. This study examined how specific symptoms affect HRQoL in individuals with PCC compared to those who had COVID-19 without PCC and those never infected. METHODS: A cross-sectional survey was conducted among a nationally representative sample of 1,813 French adults through telephone and online interviews. Participants were grouped according to WHO PCC criteria, based on infection status and 31 persistent symptoms. HRQoL was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS-29), and impairment was defined as having at least two affected domains. Logistic regressions adjusted for confounders were used to assess associations. RESULTS: Among 1,813 participants (365 with PCC, 1,270 previously infected without PCC, 178 never infected), impaired HRQoL was significantly more frequent in with PCC (36%) than in those previously infected without PCC or never infected (adjusted odds ratio: 2.02; 95% CI 1.19-3.42]). The symptoms most strongly associated with HRQoL impairment in PCC were anxiety (OR 3.75; 95% CI: 1.80-7.80), joint pain (OR 2.31; 95% CI: 1.15-4.65), and sleep disturbances (OR 2.14; 95% CI 1.08-4.25), whereas fatigue, shortness of breath, and memory issues had a weaker association with impaired HRQoL in PCC than in other groups. CONCLUSION: PCC, and particularly joint pain, anxiety and sleep disturbance, are associated with impaired HRQoL. Targeted interventions for these symptoms may improve well-being in affected individuals.