Objective To evaluate the micro-RNA (miRNA) expression profile in patients with early psoriatic arthritis (PsA) in order to assess the role of miRNAs as potential PsA biomarkers. Methods The expression of 723 mature miRNAs in peripheral blood mononuclear cells of early PsA patients in comparison with early-rheumatoid arthritis (ERA) patients and healthy controls (HC) was evaluated using a miRNA microarray. All patients had active disease and were na ve from treatment. The results were validated for a specific miRNA (miR-2I-5p) in the entire series of patients plus an additional group of early PsA, ERA and HC using droplet digital PCR. Results In PsA, microarray analysis revealed a distinct pattern of 19 (vs. HC) and 48 (vs. ERA) deregulated miRNAs (p<0.05). The significant up-regulation of miR-21-5p both in early PsA and in ERA in comparison with HC was validated and confirmed. In PsA, miR-2I-5p was found significantly down regulated after 12 weeks of therapy, which significantly correlated with the reduction of DAPSA score. Conclusion In early PsA, a 19- (vs. HC) and 48- (vs. ERA) miRNA signature was identified. A differential expression of miRNAs in patients with active disease makes them attractive biomarkers of psoriatic disease. MiR-2I-5p was found up-regulated both in early PsA and ERA, a finding which highlights its role in the inflammatory process in general and its potential role as a therapeutic target in different inflammatory disorders. A potential role of miR-2 I-5p as a response to treatment biomarker in early PsA has been identified.