Hemophagocytic lymphohistiocytosis (HLH) is generally recognized as a rapidly progressive syndrome of excessive immune activation and a cytokine storm. Diffuse large B-cell lymphoma (DLBCL), a prevalent subgroup of non-Hodgkin lymphoma, represents a common trigger of HLH. Due to the overlap in clinical manifestations between HLH and the underlying lymphoma, it is challenging to identify secondary HLH (sHLH) in DLBCL patients early. To elucidate the differences between DLBCL with HLH (DLBCL-HLH) and DLBCL without HLH (DLBCL-non-HLH), we comparatively analyzed the clinical parameters and serum cytokines in patients with DLBCL-HLH or DLBCL-non-HLH. Serum levels of interleukin (IL)-2, IL-4, IL-6, IL-8, IL-1 beta, IL-17 A, IL-10, IL-12P70, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IFN-alpha in 8 patients with DLBCL-HLH and 51 patients with DLBCL-non-HLH were measured by cytometric bead array. Compared to patients with DLBCL-non-HLH, those with DLBCL-HLH had significantly elevated lactate dehydrogenase (LDH) levels, increased serum ferritin levels, raised liver transaminases, a higher proportion of lymphoma bone marrow involvement, significantly decreased albumin levels, and reduced peripheral blood cell counts. Both in patients with DLBCL-HLH and those with DLBCL-non-HLH, serum levels of IL-6 and IL-10 were elevated. However, these cytokine levels were significantly higher among patients with DLBCL-HLH. In particular, when the level of IL-10 > 180.70 pg/ml, the sensitivity and specificity of the diagnosis of DLBCL-HLH were 87.50 % and 96.08 %, respectively. Interestingly, in patients with DLBCL-non-HLH, we observed that IL-10 positively correlated with serum ferritin levels (r = 0.768, P < 0.001), and negatively correlated with hemoglobin concentrations and platelet counts (r = -0.388, P = 0.005; r = -0.412, P = 0.003). Taken together, our results revealed that elevated serum IL-10 levels are significantly associated with sHLH in DLBCL patients, suggesting its potential as a diagnostic biomarker. High serum IL-10 levels, combined with bone marrow involvement by lymphoma, high lactate dehydrogenase, decreased albumin levels, and HLH diagnostic criteria such as increased ferritin levels and cytopenia, might boost the early identification of DLBCL-HLH.