Two sensitive and reproducible methods are described for the quantitative determination for the simultaneous estimation of cefixime trihydrate and ambroxol hydrochloride. The first method was based on HPTLC followed by densitometric measurements of their spots at 254 nm. The separation was on HPTLC aluminium sheets of silica gel 60 F254 using acetonitrile: methanol: triethylamine (8.2:1:0.8, v/v/v) as mobile phase. The linear regression analysis was used for the regression line in the range of 200–1000 ng spot^-1 for cefixime and ambroxol, respectively. This system was found to give compact spots for cefixime and ambroxol, after development. The second method was based on HPLC separation of the two drugs on the column [C18 (5µ, 25 cm×4.6 mm, i.d.)] at ambient temperature using a mobile phase consisting of acetonitrile: methanol (50:50, v/v). Quantitation was achieved with UV detection at 254 nm based on peak area with linear calibration curves at concentration ranges 4–18 and 4–28μg ml^-1 for cefixime and ambroxol, respectively. Both methods have been successively applied to pharmaceutical formulation. No chromatographic interference from the tablet excipients was found. Both methods were validated in terms of precision, robustness, recovery and limits of detection and quantitation.