The effects of low dose prednisone (PD) alone or in combination with leflunomide (LEF) were tested on inflammatory gene expression in early rheumatoid arthritis (RA). Ten RA patients were assigned as group A (untreated)and group B (pretreated with PD 5 mg/day for 3 months -T0). Therefore, both groups were treated with LFN (20mg/day). Expression ratio of 34 inflammatory genes was detected by microarray analysis in early RA patients and CNT (5), before (T0), and after 3 months (T1) of combined therapy (PN+LFN). At T0, 17 genes linked with arthritis were found altered in early RA, (A and B groups), compared to CNT. At T1 in the group A, 41% of genes were found unchanged, 12% upregulated, and 47% downregulated, whereas in the group B, 65% of genes were found unchanged, 6% upregulated, and 29% downregulated. The results suggest that the combination of PN and LEF seems to play a synergistic effect by modulating some inflammatory genes in early RA.