AIMS: To compare tissue concentrations of diclofenac resulting from topical and oral applications of diclofenac according to clinically recommended prescriptions. METHODS: Diclofenac sodium was applied to 14 subjects (four male and 10 female), who were scheduled to undergo knee arthroplasty due to osteoarthritis, according to the oral or topical prescription (a capsule containing 37.5 mg diclofenac sodium or two tapes containing a total of 30 mg diclofenac sodium). At 12 h after prescription, the diclofenac concentration in the fat, muscle and synovial tissues was measured with liquid chromatography and mass analysis. RESULTS: The diclofenac concentration in the muscle was significantly higher (P = 0.0196) after topical application (average 9.29 ng ml(-1)) than after oral application (0.66 ng ml(-1)), whereas there was no significant difference in the plasma diclofenac level (4.70 and 6.63 ng ml(-1)) between the two applications. The concentration in the synovial membrane was significantly (P = 0.0181) lower in the topical application (4.99 ng ml(-1)) than in the oral application (15.07 ng ml(-1)). CONCLUSIONS: Whereas plasma levels resulting from topical and oral applications of diclofenac according to clinically recommended prescriptions were comparable, concentration levels in the muscle and synovial tissues were different.