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Chronic inflammatory diseases are increasing in developed societies, thus new anti-inflammatory approaches are needed in the clinic. Synthetic peptides complexes can be designed to mimic the activity of anti-inflammatory mediators, in order to alleviate inflammation. Here, we evaluated the anti-inflammatory efficacy of tethered peptides mimicking the interleukin-1 receptor antagonist (IL-1Ra) and the heat-shock protein 70 (HSP70). We tested their biocompatibility and anti-inflammatory activity in vitro in primary human monocytes and differentiated macrophages activated with two different stimuli: the TLR agonists (LPS + IFN-γ) or Pam3CSK4. Our results demonstrate that IL-1Ra and HSP70 synthetic peptides present a satisfactory biocompatible profile and significantly inhibit the secretion of several pro-inflammatory cytokines (IL-6, IL-8, IL-1β and TNFα). We further confirmed their anti-inflammatory activity when peptides were coated on a biocompatible material commonly employed in surgical implants. Overall, our findings support the potential use of IL-1Ra and HSP70 synthetic peptides for the treatment of inflammatory conditions. The biocompatibility and anti-inflammatory activity of the peptides designed to mimic IL-1Ra or HSP70 were tested in vitro following three different protocols. The treatment of human primary monocytes (1) or macrophages (2) with the tethered peptides (mimicking IL-1Ra or HSP70) and exposure to TLR agonist stimulation (LPS + IFN-γ or Pam3CSK4) for 24 h, reduce the production of the pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNFα. The tethered peptides applied for 5 days during monocyte-to-macrophage differentiation (3) also prevent the secretion of the same cytokines. Overall, we demonstrate the anti-inflammatory activity of IL-1Ra or HSP70 peptide-mimics and therefore their potential use to treat inflammatory disorders. [Display omitted] • Synthetic peptide complexes mimicking IL-1Ra or HSP70 are non-toxic towards human primary monocytes and macrophages. • IL-1Ra and HSP70 tethered peptides significantly impair the production of IL-6, IL-8, IL-1β and TNFα. • PCU discs coated with IL-1RA or HSP70 peptides could be tested as implant for patients with inflammatory disorders. [ABSTRACT FROM AUTHOR]