BACKGROUND: A NOVEL AND FAST METHOD FOR SIMULTANEOUS DETERMINATION OF ACETAMINOPHEN, IBUPROFEN AND CAFFEINE IN REAL SAMPLES SUCH AS HUMAN PLASMA AND DRUG SAMPLES WAS DEVELOPED BY USING CHEMOMETRICS METHODS. ALL FACTORS EFFECTING ON THE SENSITIVITY WERE OPTIMIZED. THE SIMULTANEOUS DETERMINATION OF ACETAMINOPHEN, IBUPROFEN AND CAFFEINE MIXTURES BY USING SPECTROPHOTOMETRIC METHOD IS DIFFICULT PROBLEM, DUE TO THE SPECTRAL INTERFERENCES. THE WAVELET ORTHOGONAL SIGNAL CORRECTION WITH PLS (WOSC-PLS) METHOD WAS THEN APPLIED FOR SIMULTANEOUS DETERMINATION OF THESE DRUGS METHODS: STOCK SOLUTIONS OF ACETAMINOPHEN, IBUPROFEN AND CAFFEINE (1000 MG ML-1) WERE PREPARED. A UNIVERSAL BUFFER SOLUTION (PH 7.0) WAS PREPARED DAILY. A HEWLETT-PACKARD 8453 DIODE ARRAY SPECTROPHOTOMETER WAS USED FOR UV-VISIBLE SPECTRA ACQUISITION. ALL COMPUTATIONS FOR THIS WORK WERE PERFORMED IN MATLAB VERSION 8.1 ON A PERSONAL COMPUTER. PLS, OSC, WOSC PROGRAMS WERE OBTAINED USING THE PLS_TOOLBOX VERSION 4.0 FROM EIGENVECTOR RESEARCH INC. ALL DATA WERE MEAN CENTERED BEFORE USE FOR PLS, OSC-PLS AND WOSC-PLS MODELING.RESULTS: UNDER OPTIMIZED CONDITIONS, THE CALIBRATION CURVES WERE LINEAR IN THE RANGE OF 0.1-9.0, 1.0-15.0 AND 0.1-10.0 MG L-1 FOR ACETAMINOPHEN, IBUPROFEN AND CAFFEINE, RESPECTIVELY. LIMITS OF DETECTION WERE 0.04, 0.26 AND 0.04 MGL-1, RESPECTIVELY. THE RMSEP FOR ACETAMINOPHEN, IBUPROFEN AND CAFFEINE WITH PLS, OSC-PLS AND WOSC-PLS METHODS WERE 0.871, 0.685, 0.729 AND 0.124, 0.109, 0.112 AND 0.056, 0.031, 0.036, RESPECTIVELY. THE CAPABILITY OF THE METHOD FOR THE ANALYSIS OF REAL SAMPLES WAS EVALUATED BY THE DETERMINATION OF THESE DRUGS IN HUMAN PLASMA AND PHARMACEUTICAL SAMPLES WITH SATISFACTORY RESULTS.CONCLUSION: THE DEVELOPED METHOD IS SIMPLE, EFFECTIVE AND SENSITIVE AND VERY SUITABLE FOR DETERMINATION OF DRUGS. IN ORDER TO OVERCOME THE DRAWBACK OF SPECTRAL INTERFERENCES, WOSC-PLS AND OSC-PLS APPROACHES WERE APPLIED AND COMPARED. ANALYSIS OF THE RESULTS FOR TERNARY MIXTURES SHOWED THAT THE WOSC-PLS METHOD WAS MORE EFFECTIVE IN ENHANCING SUBSEQUENT PLS MODELS THAN PLS OR OSC-PLS METHODS.