Background. Secondary hemophagocytic syndrome (SHPS) and sepsis, although very similar in their clinical manifestations and laboratory parameters, essentially differ in terms of methods of their treatment. SHPS therapy is aimed at immunosuppression, whereas in sepsis anti-infectious treatment is required. To choose the correct therapy a rapid differential diagnosis is necessary. Aim. Search and analysis of criteria of differential diagnosis between SHPS and sepsis. Materials & Methods. The data of 102 patients were analyzed: 55 SHPS patients (median age 60 and range 18-81 years) and 47 sepsis patients (median age 60 and range 18-89 years). SHPS was diagnosed on the basis of HLH-2004 and H-Score criteria. Sepsis was confirmed by documented inflammatory lesions and systemic inflammatory reactions. Microbiologically confirmed sepsis was reported in 10 (21 %) patients. In all sepsis patients multiple organ failure was identified. Results. The study of SHPS and sepsis groups revealed significant differences (p < 0.05) in the levels of C-reactive protein, procalcitonin, creatinine, albumin, and sodium. It was also found out that splenomegaly rate and the levels of triglycerides, ferritin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in SHPS were significantly higher than in sepsis, but the levels of glycosylated ferritin (%GF), fibrinogen, leukocytes, neutrophils, and thrombocytes were lower. The following medians (quartiles 1-3) were reported in SHPS and sepsis, respectively: triglycerides (mmol/L) were 3.1 (2.3-3.8) and 1.5 (0.8-2.7), total ferritin (ng/mL) was 7,170 (3,159.2-12,551.0) and 1,274 (559.0-3,041.5), %GF was 26.5 (16.7-37.3) and 54.5 (37.7-71.8), fibrinogen (g/L) was 2.8 (1.4-4.4) and 5.3 (2.8-6.8), ALT (IU/L) was 50 (20-102) and 30 (15.3-55.5), AST (IU/L) was 66 (40.0-105.6) and 36 (24.678.0), leukocytes (x109/L) were 3.7 (2.1-5.5) and 8.9 (6.5-14.5), thrombocytes (X109/L) were 56 (25.2-93.5) and 157 (97-308). According to ROC analysis the areas under the curve were as follows: 0.88 for neutrophil level, 0.85 for total ferritin, %GF, leukocytes, and thrombocytes, 0.74 for triglycerides, 0.71 for fibrinogen, 0.65 for sodium, and 0.61 for ALT and AST. Conclusion. In differential diagnosis between SHPS and sepsis most important are the levels of total ferritin, its glycosylated fraction, and triglycerides; less important are fibrinogen, neutrophils, thrombocytes and spleen size. As diagnosis and differential diagnosis between SHPS and sepsis are based on the sum total of clinical and laboratory markers, none of the specified characteristics can serve as a reliable parameter if taken separately.