Etodolac is a non-steroidal anti-inflammatory drug with preferential inhibition of cyclooxigenase-2 and is widely used in the management of pain in patients with inflammatory arthritis. Etodolac is available as a racemic mixture of (−)-(R)-Etodolac and (+)-(S)-Etodolac; cyclooxigenases inhibition is attributed to (+)-(S)-Etodolac. According to our knowledge, this is the first method for determination of etodolac enantiomers in plasma using LC–MS/MS. Plasma extraction were performed with 25 μL of plasma and 1 mL of n-hexane:ethyl acetate (95:5); racemic ibuprofen was used as internal standard. Resolution of enantiomers were performed in a Chiralcel®OD-H column; deprotonated [M-H]− and their respective ion products were monitored at transitions of 286 > 242 for etodolac enantiomers and 205 > 161 for ibuprofen. The quantitation limit was 3.2 ng/mL for both enantiomers in plasma. The method was applied to study the pharmacokinetics of etodolac enantiomers after the administration of a 300 and 400 mg dose of racemic drug to a healthy volunteer. Analysis of plasma samples showed higher plasma concentration of (−)-(R)-Etodolacfor both doses (300 mg dose: AUC0–∞49.80 versus 4.55 ug h/mL;400 mg dose: AUC0–∞ 63.90 versus 6.00 ug h/mL) with an (R)-(+)/(S)-(−) ratio of approximately 11.