The nature of C-5 substituent and the configuration at C-5 carbon of 2,3-diphenyltetrahydrofurans, with chiral centres at C-2, C-3 and C-5, show a remarkable influence on their COX-2 inhibition and selectivity. Out of the eight compounds investigated here, 1b with COOH group and R* configuration at C-5, and 2d with CH2SCH2CH3 group and S* configuration at C-5 have been identified as lead molecules for further studies on COX-2 inhibition.