The kinetic and thermodynamic effects of aspirin and diclofenac on the activity of adenosine deaminase (ADA) were studied in 50 mM phosphate buffer pH ¼ 7.5 at 27 and 378C, using UV-Vis spectrophotometry and isothermal titration calorimetry (ITC). Aspirin exhibits competitive inhibition at 27 and 378C and the inhibition constants are 42.8 and 96.8 mM respectively, using spectrophotometry. Diclofenac shows competitive behavior at 278C and uncompetitive at 378C with inhibition constants of 56.4 and 30.0 mM, at respectively. The binding constant and enthalpy of binding, at 278C are 45 mM, 2 64.5 kJ/mol and 61 mM, 2 34.5 kJ/mol for aspirin and diclofenac. Thermodynamic data revealed that the binding process for these ADA inhibitors is enthalpy driven. QSAR studies by principal component analysis implemented in SPSS show that the large, polar, planar, and aromatic nucleoside and small, aromatic and polar non-nucleoside molecules have lower inhibition constants.