||BACKGROUND: The cause of chronic fatigue syndrome (CFS) is unknown but is thought to be associated with immune abnormalities or infection. Because cancer can arise from similar conditions, associations between CFS and cancer were examined in a population-based case-control study among the US elderly. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare registry data, approximately 1.2 million cancer cases and 100,000 controls (age range, 66-99 years; 1992-2005) were evaluated. CFS was identified in the period more than 1 year prior to selection, using linked Medicare claims. Unconditional logistic regression was used to estimate the odds ratios (ORs) comparing the CFS prevalence in cases and controls, adjusting for age, sex, and selection year. All statistical tests were 2-sided. RESULTS: CFS was present in 0.5% of cancer cases overall and 0.5% of controls. CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL) (OR = 1.29, 95% confidence interval [CI] = 1.16-1.43, P = 1.7 × 10(-6) ). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR = 1.34, 95% CI = 1.12-1.61), marginal zone lymphoma (OR = 1.88, 95% CI = 1.38-2.57), and B cell NHL not otherwise specified (OR = 1.51, 95% CI = 1.03-2.23). CFS associations with NHL overall and NHL subtypes remained elevated after excluding patients with medical conditions related to CFS or NHL, such as autoimmune conditions. CFS was also associated, although not after multiple comparison adjustment, with cancers of the pancreas (OR = 1.25, 95% CI = 1.07-1.47), kidney (OR = 1.27, 95% CI = 1.07-1.49), breast (OR = 0.85, 95% CI = 0.74-0.98), and oral cavity and pharynx (OR = 0.70, 95% CI = 0.49-1.00). CONCLUSIONS: Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL.