Two variants of partial least-squares methodology (PLS-1 and PLS-2) have been used for the analysis of ternary and quaternary mixtures of acetaminophen-acetylsalicylic acid-codeine and caffeine, respectively. This methodology permits the simultaneous quantification of the aforementioned drugs even with closely overlapping spectral bands without any separation step. The concentration ranges are 4.0–12.0, 0.2–1.0 and 4.0–12.0 μg·ml−1for acetaminophen-acetylsalicylic acid-codeine and 10.0–20.0, 6.0–16.0, 1.0–5.0 and 0.2–1.0 μg·ml−1for acetaminophen-acetylsalicylic acid-caffeine and codeine, respectively. A systematic study of the experimental data by applying an exhaustive statistical analysis to demostrate the validity of the proposed methods is presented. The results of the determination of these drugs in pharmaceutical preparations are also presented. The analytical results were quite good in all cases.