Three simple, specific, accurate and precise chemometric methods have been developed for the analysis of paracetamol and orphenadrine citrate in their mixture form without prior separation. CLS, PLS and PCR methods were used for simultaneous determination of paracetamol and orphenadrine citrate by using different sets of data in which better results were produced. The validity of these chemometrics has been carried out by using 8 synthetic mixtures for determination of the power of prediction for each method. Latent variable number is different from one model to another concurrent with changing the set of data. PRESS (predicted residual error sum of squares) and RMSEP (Root mean square error of prediction) were used for the comparison between different methods and for determination the predictive power of each set of data. Statistical comparison between the proposed chemometric methods was also performed.