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To explore the influence of contextual factors on health-related quality of life (HRQoL), which is sometimes used as an indicator of quality of care, we examined the association of neighborhood socioeconomic status (NSES) and trajectories of HRQoL after hospitalization for acute coronary syndromes (ACS).We studied 1481 patients hospitalized with acute coronary syndromes in Massachusetts and Georgia querying HRQoL via the mental and physical components of the 36-item short-form health survey (SF-36) (MCS and PCS) and the physical limitations and angina-related HRQoL subscales of the Seattle Angina Questionnaire (SAQ) during hospitalization and at 1-, 3-, and 6-month postdischarge. We categorized participants by tertiles of the neighborhood deprivation index (a residence-census tract-based measure) to examine the association of NSES with trajectories of HRQoL after adjusting for individual socioeconomic status (SES) and clinical characteristics.Participants had mean age 61.3 (SD, 11.4) years; 33% were female; 76%, non-Hispanic white; 11.2% had household income below the federal poverty level. During 6 months postdischarge, living in lower NSES neighborhoods was associated with lower mean PCS scores (1.5 points for intermediate NSES; 1.8 for low) and SAQ scores (2.4 and 4.2 points) versus living in high NSES neighborhoods. NSES was more consequential for patients with lower individual SES. Individuals living below the federal poverty level had lower average MCS and SAQ physical scores (3.7 and 7.7 points, respectively) than those above.Neighborhood deprivation was associated with worse health status. Using HRQoL to assess quality of care without accounting for individual SES and NSES may unfairly penalize safety-net hospitals.