The aim of this study was the assessment of blood and synovial levels of diclofenac after repeated epicutaneous dosing with DHEP plasters in patients with joint effusion. To eight volunteers suffering from monolateral knee joint effusion, DHEP plasters containing 180 mg DHEP each, were applied on the affected knee b.i.d. (at 8 a.m. and 8 p.m.) for 4 consecutive days (8 doses) and only at 8 a.m. of the 5th day (9th dose). Plasters were left on the affected area until the following application or for 12h the 5th day. Venous blood samples were collected immediately before the first dosis and 1, 4 and 8 hours after the 9th application, while synovial fluid (SF) from the affected knee joint was collected at the beginning of the study and at 4 hours after the 9th DHEP plaster application. Unchanged diclofenac was measured in plasma and SF by means of a GLC-mass spectrometry technique. Low but durable levels of diclofenac were obtained at each collection after dosing in plasma. Detectable SF concentrations of diclofenac at the 4th hour of the 9th application were obtained, thus indicating the diffusion of diclofenac into the synovial liquid. The authors conclude that the topical application of DHEP plaster b.i.d. for 4 days allows measurable levels of diclofenac to be obtained in the underlying affected joint, without producing elevated circulating blood concentrations of diclofenac, thus greatly reducing the risk of possible systemic side effects.