Three methods are developed for the determination of two multicomponent mixtures containing guaiphenesine (GU) with salbutamol sulfate (SL), methylparaben (MP) and propylparaben (PP) [mixture 1]; and acephylline piperazine (AC) with bromhexine hydrochloride (BX), methylparaben (MP) and propylparaben (PP) [mixture 2]. The resolution of the two multicomponent mixtures has been accomplished by using numerical spectrophotometric methods such as partial least squares (PLS-1) and principal component regression (PCR) applied to UV absorption spectra of the two mixtures. In addition HPLC method was developed using a RP 18 column at ambient temperature with mobile phase consisting of acetonitrile–0.05M potassium dihydrogen phosphate, pH 4.3 (60:40, v/v), with UV detection at 243nm for mixture 1, and mobile phase consisting of acetonitrile–0.05M potassium dihydrogen phosphate, pH 3 (50:50, v/v), with UV detection at 245nm for mixture 2.The methods were validated in terms of accuracy, specificity, precision and linearity in the range of 20–60μgml −1 for GU, 1–3μgml −1 for SL, 20–80μgml −1 for AC, 0.2–1.8μgml −1 for PP and 1–5μgml −1 for BX and MP. The proposed methods were successfully applied for the determination of the two multicomponent combinations in laboratory prepared mixtures and commercial syrups.