Early predictors of fatal leptospirosis and the role of pathogen lineages remain poorly defined, limiting clinical risk stratification, genomic surveillance, and public health response in leptospirosis-endemic settings. We conducted a multicenter prospective cohort study of hospitalized patients with suspected leptospirosis in Thailand during 2015-2024. Among 459 patients with laboratory-confirmed cases, 25 (5.4%) died during hospitalization. Older age, higher total bilirubin, and higher leptospiremia were independently associated with in-hospital death, and a combined model demonstrated good discriminatory performance. We performed targeted amplicon sequencing analysis directly on clinical samples and whole-genome sequencing on available isolates. Genomic analysis identified Leptospira interrogans as the predominant species; clonal group 272 sequence type 34 was the predominant lineage and was observed in all patients with fatal cases for whom genomic data were available. Our findings support integration of clinical predictors and pathogen load for early risk stratification and highlight the potential value of genomic surveillance in leptospirosisendemic settings.
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