High performance liquid chromatography procedures using non-porous ODS columns were developed for the assay of aspirin-caffeine-butalbital (mixture 1) and acetaminophen-caffeine-butalbital (mixture 2). The separation and quantitation of Mixture 1 were achieved on a 3.0 μm non-porous silica ODS column at ambient temperature using a mobile phase of 98:2 v/v 50 mM phosphate buffer pH 3.0-acetonitrile at a flow rate of 1.5 mL/min with detection at 220 nm. The method showed linearity for aspirin-caffeine-butalbital in the 325–6500, 40–800, and 50–1000 ng/mL ranges, respectively. Intra- and inter-day RSD values were 0.19–1.72% and 1.30–1.49% for aspirin, 0.08–1.17% and 0.06–1.09% for caffeine, and 0.09–1.55% and 0.07–2.10% for butalbital, respectively. Accuracy of intra and inter-day were in the 0.70–1.27% and 0.20–1.13% for aspirin, 0.05–0.06% and 0.004–0.09% for caffeine, and 0.02–0.09 and 0.02–0.05% for butalbital, respectively.