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OBJECTIVES: To estimate the synovial membrane penetration index of celecoxib and etoricoxib, and determine their impact on pain visual analogue score (VAS). METHODS: Patients with inflammatory synovial fluid accumulation of the knee joint were randomized in three age- and gender-matched groups of 17 patients each: the celecoxib treated group, the etoricoxib treated group, and the control group. Dosages were 100mg b.i.d. for celecoxib, 90mg o.d. for etoricoxib, and no medication in the control group. The participants completed the pain VAS, and blood and synovial fluid samples were collected at baseline and seven days later at the time of C_max for each drug. Celecoxib and etoricoxib levels were determined in serum and synovial fluid samples by UPLC coupled to ICP-MS. Identification of compounds was performed by QTOF-MS.RESULTS: After serum and synovial fluid drug concentration determination, the estimated penetration index was 23.3% (SD 32.8) for celecoxib and 49.5 % (SD 21.1) for etoricoxib, (p=0.031). In the 2 coxib groups, statistically significant reduction of pain VAS was detected (p<0.001), but only marginally in the control group (p=0.047). Etoricoxib was superior compared to celecoxib in reducing pain, as determined by VAS (p=0.02). No correlation was found between the synovial membrane penetration index of either drug and pain improvement. CONCLUSION: Etoricoxib had a better penetration index in the synovial fluid and stronger analgesic effect than celecoxib in the dosage used in patients with active inflammatory arthritis.