Mixed-level orthogonal array design (OAD) as a chemometric method has been employed to optimize liquid Chromatographic (LC) conditions for the separation of environmental pollutants. Six parameters were examined by OAD, namely reversed-phase (C 18) LC columns from different manufacturers, content of methanol and acetonitrile in the mobile phase, initial time-duration of a fixed mobile phase composition, time-duration of a gradient elution programme, and mobile phase flow rate. The optimization of these parameters for the determination of eleven priority substituted phenols was carried out to demonstrate the applicability of mixed-level OAD in environmental analytical chemistry in which the use of trial-and-error procedures is often unsatisfactory due to sample complexity. The advantages and the disadvantages of mixed-level OAD were discussed.