Pigmented villonodular synovitis (PVNS) is a rare pre-malignant disease that require aggressive treatment as surgical synovectomy, eventually followed by radiosynovectomy. Nevertheless, the disease often reoccurs after these treatments. To determine the safety and efficacy of intra-articular (IA) TNFalpha blockade with etanercept (ETN), before extended arthroscopic synovectomy, in severe PVNS of the knee, two patients, (a 26-year-old man with B27+ undifferentiated spondylarthropathy and a 32-year-old femal with seronegative oligoarthritis), affected by diffuse knee PVNS (diagnosis made by histological examination), resistant to IA corticosteroid injections and to repeated arthroscopic synovectomy, were submitted, after protocol approval by human research committee and patient's written informed consent to intra-articular etanercept (IA-ETN) treatment with a different dosage schedule: 12.5 mg weekly IA-ETN injection for 4 weeks, followed by extended arthroscopic synovectomy and of 25 mg IA-ETN injection for 4 weeks, respectively. Previous DMARDs treatment was continued in stable appropriate doses. Any adverse events were recorded throughout the study. The following parameters were considered as clinical endpoints: 1) Knee Joint Index (KJI: range 0-14); 2) Thompson index (THI: range 0-9) At the study entry and at the end of follow-up, high frequency ultrasound grey scale synovial thickening (US-ST) was also assessed. No adverse events were observed due to IA-ETN and to arthroscopic synovectomy. Marked improvement of knee disease activity over time and sustained functional recover was obtained. US-ST evaluation before treatment initiation and at the end of follow-up confirmed the regression of knee joint synovial proliferation.