Two HPLC methods are introduced in this paper for the simultaneous determination of doxorubicin hydrochloride (DOX) and 5-fluorouracil (5-FU), combination I, and of cytarabine (CYT) and etoposide (ETO), combination II, as co-administered drugs. In both combinations, a 250mm×4.6mm C-18 column is used. The mobile phase for combination I consists of a mixture of acetonitrile and 0.05M disodium hydrogenphosphate (50:50, v/v) containing 0.1% sodium laurylsulfate (SLS) adjusted to pH 3.7 at a flow rate 1ml/min, with UV detection at 260nm and ambient temperature. For combination II, the mobile phase consists of a mixture of 0.02M sodium dihydrogenphosphate aqueous solution adjusted to pH 6.0 (with 0.2M orthophosphoric acid or sodium hydroxide) and acetonitrile in a ratio of (7:3) at a flow rate 1ml/min, with UV detection at 254nm and ambient temperature. The methods also permitted the determination of methyl hydroxybenzoate (MHB) which is used as a preservative in DOX vials, combination I, and of benzyl alcohol (BZA) preservative in ETO vials, combination II. The proposed HPLC methods were successfully applied to the determination of the investigated drugs, of the two combinations, both in injection solutions and spiked human plasma samples with high precision and accuracy. Linearity, validation, accuracy, precision, limits of detection, limits of quantitation, and other aspects of analytical validation are presented in the text.