This study was conducted to test the safety of intra-articular tumor necrosis factor alpha (TNF-) antagonists in small joints with arthritis. A dose of 2-8 mg etanercept was given intra-articularly guided by ultrasonography (US) in 26 patients with a flare of arthritis in a particular joint (16 wrists, two elbows, two ankles, six finger joints). Primary end points were imaging analyses by independent investigators: US-Doppler measurements were performed in all patients before and after the injection and MRI before and after were obtained in nine patients. The only adverse event was a case of swelling of the hand lasting 2 days after a wrist injection. Two patients had a supplementary glucocorticoid injection and were excluded from efficacy analysis after 4 days and 3 weeks, respectively. VAS for pain decreased after 1 week in 23 of 25 patients (median 0.62), and after 1 month in 14 of 24 patients (median 0.60). No significant changes were seen in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). On MRI, all nine cases tested had a reduction in synovial thickness (P=0.008) and US Doppler signals diminished after treatment (resistance index (RI) P=0.02, pixels P=0.09). In conclusion, intra-articular injection of etanercept gave no noticeable adverse events.