The present study was designed to investigate the effects of a novel CaMKII inhibitor SMP‐114, which was effective in a collagen‐induced arthritis model in rats, on rheumatoid synovial fibroblasts. Rheumatoid synovial fibroblasts (RSF) were cultured under pro‐inflammatory (IL‐1β stimulation) and hypoxic conditions. Protein and mRNA expression of HIF‐1α and the effects of inhibitors of the CaMKII‐, PI3K‐, and ERK pathway on VEGF and IL‐6 production were analyzed. Stimulation under hypoxic conditions induced higher expression of HIF‐1α and VEGF mRNA than treatment with either IL‐1β or hypoxia alone. However, incubation with a specific CaMKII inhibitor did not result in reduced VEGF production in RSF. CaMKII activation has been reported to be involved in HIF‐1α stabilization, but incubation with SMP‐114, a specific CaMKII inhibitor, had no effect on HIF‐1‐induced VEGF production by rheumatoid synovial fibroblasts.