A direct and simple first derivative spectrophotometric method has been developed for the determination of mefenamic acid and paracetamol in pharmaceutical formulations. A methanolic hydrochloric acid solution was used as solvent for extracting the drugs from the formulations and subsequently the samples were evaluated directly by derivative spectrophotometry. Simultaneous determination of both drugs can be carried out using the zero-crossing and the graphical methods. The methods do not require simultaneous equations to be solved. The calibration graphs were linear in the ranges from 1.8 × 10−6to 1.6 × 10−4M of mefenamic acid and from 4.1×10−6to 1.4 × 10−4M of paracetamol. The ingredients commonly found in commercial pharmaceutical formulations do not interfere. The proposed method was applied to the determination of these drugs in tablets.