Interleukin 10 (IL-10) exerts anti-inflammatory and immune regulatory roles through its fixation to the IL-10 receptor (IL-10R). The two subunits (IL-10Rα and IL-10Rβ) organise themselves to form a hetero-tetramer to induce the activation of the transcription factor STAT3. We analysed the activation patterns of the IL-10R, especially the contribution of the transmembrane (TM) domain of the IL-10Rα and IL-10Rβ subunits, as evidence accumulates that this short domain has tremendous implications in receptor oligomerisation and activation. We also addressed whether targeting the TM domain of IL-10R with peptides mimicking the TM sequences of the subunits translates into biological consequences. The results illustrate the involvement of the TM domains from both subunits in receptor activation and feature a distinctive amino acid crucial for the interaction. The TM peptide targeting approach also appears to be suitable for modulating the activation of the receptor through its action on the dimerization capabilities of the TM domains and thereby constitutes a potential new strategy for the modulation of the inflammation in pathologic contexts.