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Timely diagnosis of hemophagocytic lymphohistiocytosis (HLH) is critical and relies on clinical judgment. The HLH‐2004 criteria are commonly used diagnostic criteria, whereas HScore was recently developed for reactive HLH. Objective: In this external validation study, we sought to compare the diagnostic accuracy of the HLH‐2004 criteria and HScore and identify optimal cutoffs stratified by underlying etiology. Methods: In this retrospective cohort of all hospitalized adults in Alberta, Canada, (1999–2019) who had ferritin >500 ng/ml and underwent either biopsies or soluble CD25 testing, we calculated the diagnostic accuracy of HLH‐2004 and HScore for the overall population and different etiologies. Results: Of 916 patients, 98 (11%) had HLH. HLH‐2004 criteria ≥5 predicted HLH with a sensitivity of 91%, specificity of 93%, positive predictive value of 90%, and negative predictive value of 94% (c‐statistic 92%). HScore ≥169 predicted HLH with better sensitivity (96%) but reduced specificity (71%), whereas the optimal cutoff ≥200 performed comparably to HLH‐2004. HLH‐2004 criteria outperformed HScore in most etiologies, whereas HScore improved sensitivity in inflammatory/autoimmune‐HLH. The optimal cutoff of HScore was higher in hematopoietic cell transplant due to higher prevalence of fevers and cytopenias. Conclusion: HLH‐2004 criteria and HScore demonstrated excellent discriminatory power in identifying HLH. HScore may improve diagnostic accuracy in autoimmune‐HLH. [ABSTRACT FROM AUTHOR]