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The prevalence of responsiveness to initial fluid challenge among hypotensive sepsis patients is unclear. To avoid fluid overload, and unnecessary treatment, it is important to differentiate these phenotypes. We aimed to 1) determine the proportion of hypotensive sepsis patients sustaining favorable hemodynamic response after initial fluid challenge, 2) determine demographic and clinical risk factors that predicted refractory hypotension, and 3) assess the association between timeliness of fluid resuscitation and refractoriness.Secondary analysis of a prospective, multisite, observational, consecutive-sample cohort.Nine tertiary and community hospitals over 1.5 years.Inclusion criteria 1) suspected or confirmed infection, 2) greater than or equal to two systemic inflammatory response syndrome criteria, 3) systolic blood pressure less than 90 mm Hg, greater than 40% decrease from baseline, or mean arterial pressure less than 65 mm Hg.Sex, age, heart failure, renal failure, immunocompromise, source of infection, initial lactate, coagulopathy, temperature, altered mentation, altered gas exchange, and acute kidney injury were used to generate a risk score. The primary outcome was sustained normotension after fluid challenge without vasopressor titration. Among 3,686 patients, 2,350 (64%) were fluid responsive. Six candidate risk factors significantly predicted refractoriness in multivariable analysis: heart failure (odds ratio, 1.43; CI, 1.20–1.72), hypothermia (odds ratio, 1.37; 1.10–1.69), altered gas exchange (odds ratio, 1.33; 1.12–1.57), initial lactate greater than or equal to 4.0 mmol/L (odds ratio, 1.28; 1.08–1.52), immunocompromise (odds ratio, 1.23; 1.03–1.47), and coagulopathy (odds ratio, 1.23; 1.03–1.48). High-risk patients (≥ three risk factors) had 70% higher (CI, 48–96%) refractory risk (19% higher absolute risk; CI, 14–25%) versus low-risk (zero risk factors) patients. Initiating fluids in greater than 2 hours also predicted refractoriness (odds ratio, 1.96; CI, 1.49–2.58). Mortality was 15% higher (CI, 10-18%) for refractory patients.Two in three hypotensive sepsis patients were responsive to initial fluid resuscitation. Heart failure, hypothermia, immunocompromise, hyperlactemia, and coagulopathy were associated with the refractory phenotype. Fluid resuscitation initiated after the initial 2 hours more strongly predicted refractoriness than any patient factor tested.