Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. We used classification and regression tree and receiver operating curve analysis to identify the most useful diagnostic and prognostic parameters and optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3,900 U/ml) and ferritin (>1,000 ng/ml) best identified HLH-2004 defining features (sensitivity 84%, specificity 81%). Moreover, this combination, which we term the 'optimized HLH inflammatory' (OHI) index, was highly predictive of mortality (hazard ratio 4.3; confidence interval 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk that were not defined as having HLH by HLH-2004/HScore. Finally, the OHI demonstrates diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies HM patients with an inflammatory state associated with a high mortality risk and warrants further prospective validation.