CD14-positive monocytes from patients with rheumatoid arthritis (RA) are more resistant to apoptosis, which promotes their persistence at the inflammatory site and thereby contributes crucially to immunopathology. We sought to elucidate one mechanism underlying this unique pathogenesis: resistance to apoptosis and the potential involvement of miR-29b in this process. CD14-positive peripheral blood monocytes (PBMs) from RA patients were observed to be resistant to spontaneous apoptosis compared to PBMs from healthy volunteers. Intriguingly, expression of miR-29b was significantly upregulated in PBMs from RA patients than those from healthy volunteers, and this upregulation was correlated with RA disease activity. Functionally, forced expression of the exogenous miR-29b in CD14-positive Ctrl PBMs conferred resistance to spontaneous apoptosis and Fas-induced death, thereafter enhancing the production of major proinflammatory cytokines in there cells. Following identification of the potential miR-29b target transcripts using bioinformatic algorithms, we showed that miR-29b could directly bind to the 3'-UTR of the high-mobility group box-containing protein 1 (HBP1) and inhibited its transcription in PBMs. Importantly, stable expression of the exogenous HBP1 in differentiated THP-1 monocytes effectively abolished miR-29b-elicited resistance to Fas-induced apoptosis. Finally, among patients with RA and good clinical responses to immunotherapy, expression levels of miR-29b were significantly compromised in those treated with infliximab (a TNF-α inhibitor) but not in those treated with tocilizumab (a humanized mAb against the IL-6 receptor), pointing to a potential association between miR-29b activation and TNF-α induction. The available data collectively suggest that TNF-α-elicited miR-29b potentiates resistance to apoptosis in PBMs from RA patients via inhibition of HBP1 signaling, and testing patients for miR-29b/HBP1 expression ratios may provide more accurate prognostic information and could influence the recommended course of immunotherapy.