A stable isotope dilution gas chromatographic/negative ion chemical ionization mass spectrometric assay for diclofenac in human plasma is described. The preparation of (18O2)diclofenac and its use as an internal standard for quantitative gas chromatography/mass spectrometry is shown. A sample processing and derivatization sequence with product recovery of 84.7% was found. The method presented permits quantitative measurement of diclofenac in human plasma at the lower femtomole level. Plasma levels of diclofenac after administration of diclofenac gel were estimated.