A new group of 2,4,5-triarylimidazole derivatives, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents at the para position of C-2 phenyl ring. Among the 2,4,5-triarylimidazoles, 2- (4-hydroxy phenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-1H imidazole (11f) was identified as a selective COX-2 inhibitor (COX-2 IC50 = 0.15 lM; selectivity index = 75) that was less potent than the reference drug celecoxib (COX-2 IC50 = 0.06 lM; SI = 405). A molecular modeling study where 11f was docked in the binding site of COX-2 showed that the methylsulfonyl pharmacophore group is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518, Gly519, and Val523). The structure–activity data acquired indicate that COX-1/COX-2 inhibition is sensitive to the nature of the C-2 phenyl substituents.