Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), a member of the C-type lectin superfamily, has been reported to bind to various pathogens and several tumor cells and to participate in immunoregulation. It is still unclear whether there is a significant association between the level of DC-SIGN and non-Hodgkin lymphoma (NHL). To investigate the clinical diagnostic significance of DC-SIGN in NHL, we conducted a study with 52 NHL patients and 104 healthy individuals. Enzyme-linked immunosorbent assay and tissue microarray technology were utilized for the analysis. The serum sDC-SIGN levels in the NHL patients were significantly lower than those in the healthy controls (P=0.0019). A cutoff value of 1.499 µg/ml for sDC-SIGN predicted the presence of NHL with 78.85% sensitivity and 53.85% specificity [area under the curve (AUC)=0.6531, P=0.0019]. The serum sDC-SIGN levels in NHL patients were also significantly correlated with β2-microglobulin (P=0.0062). Moreover, tissue microarray analysis demonstrated that the expression of DC-SIGN in the lymph nodes or tissues of 96 NHL patients was significantly lower than that in 18 normal lymph nodes (P<0.0001). However, the expression of DC-SIGN in NHL displayed no significant correlation with the expression of CD20 or CD79a. In conclusion, DC-SIGN may be a promising biological molecule for clinical research on NHL, whereas the underlying roles need to be investigated in additional studies.