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Abstract Heparan sulfate (HS) interacts with a broad spectrum of inflammatory cytokines, thereby modulating their biological activities. It is believed that there is a structural‐functional correlation between each protein and sugar sequences in the HS polysaccharides, however, the information in this regard is limited. In this study, we compared the binding of four inflammatory cytokines (CCL8, IL‐1beta, IL‐2 and IL‐6) to immobilized heparin by an SPR analysis. To define the molecular base of the binding, we used a heparin pentasaccharide as representative structure to dock into the 3D‐molecular structure of the cytokines. The results show a discrepancy in KD values obtained by SPR analysis and theoretical calculation, pointing to the importance to apply more than one method when describing affinity between proteins and HS. By cluster analysis of the complex formed between the pentasaccharide and cytokines, we have identified several groups in heparin forming strong hydrogen bonds with all four cytokines, which is a significant finding. This molecular and conformational information should be valuable for rational design of HS/heparin‐mimetics to interfere cytokine‐HS interactions.