A series of cyclic 4B8M tetrapeptide immunosuppressive analogs were synthesized to evaluate effects of any single amino acid residue of 4B8M sequence (c[Pro-Pro-β3-HoPhe-Phe-]) on therapeutic potential of new analogs and analyze their structure-activity relationship. The compounds were not toxic for human peripheral blood mononuclear cells (PBMC) at 100 µg/mL and were also weakly anti-proliferative at 10 µg/mL. However, some compounds significantly inhibited phytohemagglutinin A (PHA)-induced proliferation of PBMC at 100 µg/mL. Almost all peptides inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production in human whole blood cultures. A majority of the peptides were significantly inhibitory in the model of carrageenan-induced air poach inflammation as determined by reduction of cell numbers in the exudates. We postulate that among the investigated series of compounds P26 (c[Pro-Oic-β3-HoPhe-Phe-]) and P29 (c[Pro-Tic-β3-HoPhe-Phe-]) exhibited universal immunosuppressive actions by inhibition of cell proliferation, TNF-α production and carrageenan-induced inflammation. P24 (c[Pro-Pro-β3-HoPhe-Phe(4Cl)-]), in turn, presented very selective activity by affecting only carrageenan-induced inflammation, being a laboratory model for clinical rheumatoid arthritis. In conclusion, single amino acid changes in the parent peptide sequence may generate analogs of different immunotropic profiles of potential therapeutic utility.