BACKGROUND: The rate of hospitalization for venous thromboembolism (VTE) is increasing in the United States. Although predictors of hospital-acquired VTE are well-known, triggers of VTE before hospitalization are not as clearly defined. The objective of this study was to evaluate triggers of hospitalization for VTE. METHODS AND RESULTS: A case-crossover study was conducted. Subjects were participants in the Health and Retirement Study, a nationally representative sample of older Americans. Data were linked to Medicare files for hospital and nursing home stays, emergency department visits, outpatient visits including physician visits, and home health visits from years 1991 to 2007 (n=16 781). The outcome was hospitalization for venous thromboembolism (n=399). Exposures during the 90-day period before hospitalization for VTE were compared with exposures occurring in 4 comparison periods. Infection was the most common trigger of hospitalization for VTE, occurring in 52.4% of the risk periods before hospitalization. The adjusted incidence rate ratios (IRRs; 95% confidence interval) were 2.90 (2.13, 3.94) for all infection, 2.63 (1.90, 3.63) for infection without a previous hospital or skilled nursing facility stay, and 6.92 (4.46, 10.72) for infection with a previous hospital or skilled nursing facility stay. Erythropoiesis-stimulating agents and blood transfusion were also associated with VTE hospitalization (IRR=9.33, 95% confidence interval: 1.19, 73.42; IRR=2.57, 95% confidence interval: 1.17, 5.64; respectively). Other predictors included major surgeries, fractures (IRR=2.81), immobility (IRR=4.23), and chemotherapy (IRR=5.70). These predictors, combined, accounted for a large proportion (69.7%) of exposures before VTE hospitalization as opposed to 35.3% in the comparison periods. CONCLUSIONS: Risk prediction algorithms for VTE should be reevaluated to include infection, erythropoiesis-stimulating agents, and blood transfusion.