BACKGROUND: Hospitalization is associated with microbiome perturbation-or dysbiosis-and this perturbation is more severe in patients treated with antimicrobials. We evaluated whether hospitalizations known to be associated with periods of microbiome perturbation are associated with increased risk of severe sepsis after hospital discharge. METHODS: We studied participants in the U.S. Health & Retirement Study with linked Medicare claims (1998-2010). We measured whether 3 hospitalization types associated with increasing severity of probable dysbiosis-non-infection-related hospitalization, infection-related hospitalization, and hospitalization with Clostridium difficile infection (CDI)-were associated with increasing risk for severe sepsis in the 90 days after hospital discharge. We used two study designs; the first was a longitudinal design with between-person comparisons and the second was a self-controlled case series design using within-person comparison. RESULTS: We identified 43,095 hospitalizations among 10,996 HRS-Medicare participants. In the 90 days following non-infection-related hospitalization, infection-related hospitalization, and hospitalization with CDI, adjusted probabilities of subsequent admission for severe sepsis were 4.1% (95% CI: 3.8%-4.4%), 7.1% (95% CI: 6.6%-7.6%), and 10.7% (95% CI: 7.7%-13.8%), respectively. The incidence rate ratio (IRR) of severe sepsis was 3.3 fold greater during the 90 days after hospitalizations than during other observation periods. The IRR was 30% greater after an infection-related hospitalization versus a non-infection-related hospitalization. The IRR was 70% greater after a hospitalization with CDI than an infection-related hospitalization without CDI. CONCLUSIONS: There is a strong dose-response relationship between events known to result in dysbiosis and subsequent severe sepsis hospitalization that is not present for re-hospitalization for non-sepsis diagnoses.