<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>Conclusions: Cancer survivors experience more symptom burden than non-cancer individuals, which is associated with more chronic conditions and impaired HRQOL.</jats:p> <jats:p>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.</jats:p>