This work proposes a simple and rapid analytical procedure for determination of diclofenac (DCF) in the presence of B vitamins, based on UV measurements and partial least squares (PLS). The interference of thiamine (THI) and pyridoxine (PYR) were modelled using an experimental design constructed in the ranges of 10-50 micromoll(-1) for DCF and THI and 15-75 micromoll(-1) for PYR. The procedure was repeated at five different pH values (between 3 and 6) and the best results were observed at pH 5, presenting a root mean square error of prediction (RMSEP) of 0.80 micromoll(-1) for DCF. The procedure was successfully applied to simultaneous determination of DCF, THI and PYR in synthetic mixtures and in a pharmaceutical formulation that contains a simple excipient (lactose). For determination of a more complex formulation that contains 15 different substances in the excipient, including some UV absorbing ones, the procedure was only able to determine DCF, since the excipient interferences disturbed THI and PYR predictions. Figures of merit, such as selectivity, analytical sensitivity, limit of detection and precision were determined for the DCF prediction model and the determinations were verified by an independent method, HPLC.