Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects synovial joints. Anti-TNF-alpha and anti-IL-6 receptor monoclonal antibodies are among the therapeutic approaches that have been successfully used in treatment of this disease. However, there is a need for additional and differentiated therapies, which may have advantages over the monoclonal antibody approach, including improved tissue penetration into the joints and a lower anti-drug antibody response. Here we present a generic strategy for modulating cytokine function and focus on the preclinical development of an injectable anti-IL-6 peptide for the treatment of RA. Using a combination of proprietary software, phage-display selection, and medicinal peptide-based chemistry, we designed the disulfide-rich peptide, PN-1, a potent inhibitor of IL-6. We found that PN-1, and its 40 K-PEGylated analog, PN-2, potently inhibited IL-6 induced pStat3 activation in the human monocyte cell line U937. A pharmacokinetic analysis of PN-2 demonstrated plasma half-life of >24 h, consistent with the known effect of PEGylation. Finally, we evaluated the in vivo efficacy of PN-2 in cynomologous monkey and found that PN-2 decreased the levels of the IL-6 induced biomarkers SAA and CRP in the monkey by 97% at 24 h after IL-6 challenge.