We evaluated clinically and sonographically the effects of etanercept therapy in patients with rheumatoid arthritis (RA) over 12 months of treatment. Eighteen patients affected by RA who were non-responders or partial responders to disease modifying therapy were commenced on Etanercept treatment. Before starting therapy (T0) and at 12 months (T1), the following parameters were evaluated: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS) for pain, number of painful and swollen joints, health assessment questionnaire (HAQ) and disease activity score in 28 joints (DAS 28). Musculoskeletal ultrasound (US) was performed in the following joints: second and fifth metacarpophalangeal, third interphalangeal, wrist and knee joints and a semiquantitative score (0-3) calculated and used to indicate the presence of a localised inflammatory process (synovitis, tenosynovitis, bursitis) and/or structural damage (bone erosion and cartilaginous change). An overall score was calculated based on the sum of the single scores to obtain a comprehensive score indicative of the global pathological change. The US global scores significantly reduced between T0 and T1 (p < 0.0001). The following laboratory and clinical parameters also significantly reduced: ESR (p < 0.0001), CRP (p < 0.02), VAS (p < 0.001), number of total swollen joints (p < 0.001), number of total painful joints (p < 0.01), HAQ scores (p < 0.05) and DAS 28 (p < 0.0001). A positive response to treatment with Etanercept was demonstrated both by US examination of several joints and by clinical evaluation of several parameters. US is a useful tool in the monitoring of biologic therapy in RA, assessing both inflammatory and destructive changes.