In the present work, the ratio spectra first derivative spectrophotometry is proposed for the resolution of Clopidogrel bisulphate (CLP) and Apirin (ASP) in synthetic mixtures prepared in random fashion and tablets available in 1:1 and 1:2 ratio. The calibration graph follows Beer’s law in the range of 6 to 30 μcg/ml for clopidogrel bisulphate and from 4-20 μcg/ml for aspirin. The mean recoveries & relative standard deviations were found as 99.40% & 0.442% for CLP and 100.09% and 0.905% for ASP, respectively in 1:1 ratio. Similarly the mean recoveries & relative standard deviations were found as 999.84% & 1.024% for CLP and 99.95% and 0.578% for ASP, respectively in 1:2 ratio. The graphical treatment of the overlapping spectra depends on division of the absorption spectrum of the binary mixture by a standard spectrum of one of the components and then calculating the first derivative of the ratio spectrum. These approaches were successfully applied to quantify CLP combined with ASP in tablets respectively and validated accordingly for random ratios in synthetic mixtures.