Rationale: Sepsis is a leading cause of death and disability whose heterogeneity is often cited as a key impediment to translational progress. Objective: To test the hypothesis that there are consequential and significant differences in sepsis outcomes that result from differences in a patient's clinical course leading up to sepsis hospitalization. Methods: Observational cohort study of US Health and Retirement Study (HRS) participants in Medicare (1998-2012); US Veterans Affairs (VA) beneficiaries (2009). Using latent profile analysis, we identified patient sub-types based on trajectory of pre-sepsis healthcare facility use. Subtypes were identified in the derivation cohort (1,512 sepsis hospitalizations among earlier HRS participants), then validated in two additional cohorts (1,992 sepsis hospitalizations among later HRS participants; 32,525 sepsis hospitalizations among VA beneficiaries). We measured the association between pre-sepsis path and 90-day mortality, using chi-square tests and multivariable logistic regression. Results: We identified 3 subtypes: “low use” of inpatient healthcare facilities, 84% of derivation cohort; “rising use”; 12%; and “high use”; 4%. The shape and distribution of pre-sepsis trajectories were similar in all three cohorts. In the derivation cohort, 90-day mortality differed by pre-sepsis trajectory: 38% (low use), 63% (rising use), and 48% (high use), p<0.001. This association persisted in the validation cohorts, p<0.001 for each. The rising use class remained an independent predictor of mortality after adjustment for potential confounders, including detailed physiologic data. Conclusions: In national cohorts of sepsis patients, we have shown that several distinct paths into sepsis exist. These paths, identified from trajectories of pre-sepsis healthcare use, are predictive of 90-day mortality.