BACKGROUND: CHANGEABLE SIZE Moving Window PARTIAL LEAST SQUARES (CSMWPLS) [1] IS PROPOSED TO SEARCH FOR AN OPTIMIZED SPECTRAL INTERVAL AND USED FOR SIMULTANEOUS SPECTROPHOTOMETRIC DETERMINATION OF CAFFEINE, CODEINE AND MORPHINE IN BIOLOGICAL SAMPLES BY MODELING BY PARTIAL LEAST SQUARES [2]. THE UTILIZATION OF INFORMATIVE REGIONS AIMS TO CONSTRUCT BETTER PLS MODELS THAN THOSE BASED ON THE WHOLE SPECTRAL POINTS.METHODS: STOCK SOLUTIONS OF CAFFEINE, CODEINE AND MORPHINE (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 AND CSMW PROGRAMS WERE WRITTEN BY AUTHORS. ALL DATA WERE MEAN CENTERED BEFORE USE FOR PLS AND CSMWPLS MODELING.RESULTS: UNDER OPTIMIZED CONDITIONS, THE CALIBRATION CURVES WERE LINEAR IN THE RANGE OF 0.1-10.0, 0.1-8.0 AND 0.1-3.0 MG L-1 FOR CAFFEINE, CODEINE AND MORPHINE, RESPECTIVELY. LIMITS OF DETECTION WERE 0.05, 0.06 AND 0.05 MGL-1, RESPECTIVELY. THE EXPERIMENTAL CALIBRATION MATRIX WAS DESIGNED BY MEASURING THE ABSORBANCE OVER THE RANGE 200-500 NM FOR 9 SAMPLES IN DYNAMIC RANGES OF DRUGS. THE RMSEP FOR CAFFEINE, CODEINE AND MORPHINE WITH PLS AND CSMWPLS METHODS WERE 0.129, 0.206 AND 0.023, 0.059, 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, CSMWPLS AND PLS APPROACHES WERE APPLIED AND COMPARED. ANALYSIS OF THE RESULTS FOR TERNARY MIXTURES SHOWED THAT THE CSMWPLS METHOD WAS MORE EFFECTIVE IN ENHANCING SUBSEQUENT PLS MODELS THAN PLS METHOD.