Background: To compare associations of symptom prevalence, chronic conditions, and health-related quality of life (HRQOL) between cancer survivors and non-cancer individuals using the U.S. National Health Interview Survey.Methods: Study samples comprised 604 survivors and 6,166 non-cancer individuals. Symptoms included sensation abnormality, pain, fatigue, cognitive disturbance, depression, and anxiety. Physical and mental HRQOL was measured by the Patient-Reported Outcomes Measurement Information System.Results: Compared with non-cancer individuals, survivors had higher prevalence in sensation abnormality (OR = 2.4; 95% CI = 1.9 to 3.0), pain (OR = 2.1; 95% CI = 1.7 to 2.6), fatigue (OR = 1.4; 95% CI = 1.1 to 1.8), and decremented physical HRQOL (difference = -3.7; 95% CI = -4.7 to -2.6). The prevalence of individual symptoms was significantly associated with decremented physical HRQOL [range = -5.9 (anxiety) to -8.9 (pain)] and mental HRQOL [range = -4.7 (sensation) to -8.4 (depression)]. The association between cancer experience and physical and mental HRQOL was chiefly explained by the prevalence of six symptoms and presence of chronic conditions. Pain (β = -4.0; 95% CI = -4.5 to -3.6) and ≥2 chronic conditions (β = -9.2; 95% CI = -10.2 to -8.2) significantly decremented physical HRQOL. Depression (β = -5.2; 95% CI = -5.8 to -4.6) and ≥2 chronic conditions (β = -3.3; 95% CI = -4.4 to -2.3) significantly decremented mental HRQOL.Conclusions: Cancer survivors experience more symptom burden than non-cancer individuals, which is associated with more chronic conditions and impaired HRQOL.Impacts: Interventions to manage symptom prevalence especially for older cancer survivors and survivors with more chronic conditions may improve their HRQOL outcomes. Cancer Epidemiol Biomarkers Prev; 26(7); 1124-32. ©2017 AACR.