In some instances, because of the lack of mass formation and the absence of prominent lymph node enlargement, diagnosis of lymphoma-associated hemophagocytic syndrome (LAHS) is difficult, which results in the development of progressive disease with unfavorable prognosis. Therefore, in the diagnosis of secondary hemophagocytic syndrome (HPS), markers for underlying malignant lymphoma are required. We reviewed 110 Japanese patients, including 57 LAHS cases and 53 benign disease-associated HPS cases, and demonstrated that the values of the serum sIL-2R level and sIL-2R/ferritin ratio in LAHS patients were both statistically higher than those of patients with benign disease-associated HPS. Most LAHS patients showed high values of both indices. The positive predictive value of patients showing high values of both indices for LAHS was 95.6%. On the other hand, the predictive value of patients showing low values of both indices for benign disease-associated HPS was 92.1%. We propose serum sIL-2R/ferritin ratio as a novel useful marker for predicting underlying malignant lymphoma in HPS patients.