Purpose Little is known about change in quality of life (QOL) among long-term cancer survivors. We examined change over time in QOL among long-term survivors of non-Hodgkin lymphoma and identified demographic, clinical, and psychosocial risk factors for poor outcomes. Methods Surveys were mailed to 682 lymphoma survivors who participated in a study 5 years earlier, when on average they were 10.4 years postdiagnosis. Standardized measures of QOL, perceptions of the impact of cancer, symptoms, medical history, and demographic variables were reported at both time points and examined using linear regression modeling to identify predictors of QOL over time. Results A total of 566 individuals participated (83% response rate) who were a mean of 15.3 years postdiagnosis; 52% were women, and 87% were white. One third of participants (32%) reported persistently high or improved QOL, yet a notable proportion (42%) reported persistently low or worsening QOL since the earlier survey. Participants who received only biologic systemic therapy reported improvement in physical health despite the passage of time. Older age, more comorbidity, and more or increasing negative and decreasing positive perceptions of cancer's impact were independent predictors of poor QOL. Lymphoma symptom burden, less social support, and having received a transplantation were related to negative perceptions of cancer's impact. Conclusion Moderate to severe symptom burden, limited social support, or having received a transplantation should alert the clinician to potential need for supportive services. Perceptions of cancer's impact are associated with QOL cross-sectionally and longitudinally; modifying these perceptions may thus provide a strategy for improving QOL. © 2012 by American Society of Clinical Oncology.