Objective: Antimicrobial agents in combination with anti-inflammatory drugs have been usually prescribed in both Medicine and Dentistry. However, few scientific reports support this clinical practice. The aim of this study was to evaluate the effect of betamethasone and diclofenac sodium on serum and tissue concentration of amoxicillin in rats. Methods: Four polyurethane sponges were implanted in the back skin of 48 rats. After seven days the animals were divided into 6 groups (n=8). Group 1: amoxicillin (25 mg/kg); G2: diclofenac sodium (2.5 mg/kg); G3: betamethasone (0.1 mg/kg); G4: diclofenac sodium and amoxicillin; G5: betamethasone and amoxicillin; and G6: 0.9% sodium chloride solution (1.0 mL - control group). All drugs were administered in a single dose. After 90 minutes, the granulomatous tissues of each animal were surgically removed and weighed. Blood was collected from cervical plexus, centrifuged and 10μL of serum was placed on paper discs. In order to estimate amoxicillin concentration, serum and granulomatous tissues were separately submitted to microbiological assay, which used 108cfu/mL of Staphylococcus aureus ATCC 25923 (penicillin-susceptible strain). After incubation (18 hours, 37°C) the inhibition zones were measured and compared to a regression curve. Results: No inhibition zones were observed for groups 2, 3 and 6. Tissue and serum concentrations of both G1 (4.14μ g/g and 2.06μ g/mL, respectively) and G5 (3.87μ g/g and 1.70μ g/mL, respectively) showed statistically significant differences (Kruskal-Wallis, p<0.05) in comparison to G4 (1.45μ g/g and 0.41μ g/mL, respectively). G1 and G5 did not differ significantly (p>0.05). 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