A simple and rapid HPLC method was developed and validated for simultaneous determination of two antipsychotic drugs, olanzapine and aripiprazole, in spiked human plasma. Optimization studies were performed using experimental design approach. The most important analysis parameters were selected using fractional factorial design and optimum levels of these parameters were determined with Box-Behnken design. Separation was achieved on a monolithic column (Rp-18, 100-4.6 mm) set at 35 degrees C with a flow rate of 0.8 ml/min. Gradient elution was performed with a mobile phase consisting of phosphate buffer (pH 3.14, 20 mM) and acetonitrile. Retention times of olanzapine and aripiprazole were 2.34 and 6.90 minutes, respectively. The method was linear in the range of 0.125-50.0 mu g/ml for olanzapine and 0.500-50.0 mu g/ml for aripiprazole. The quantification limits for olanzapine and aripiprazole were found 0.069 and 0.498 mu g/ml, respectively. The method was found accurate and precise based on recovery values, which were between 99-102% and relative standard deviations, which were lower than 2%. Robustness of the method and the stability of analytes were also investigated.