The present paper deals with the development of a rapid and feasible high-performance liquid chromatographic method for the determination of trazodone and its main active metabolite 3-(1-clorophenyl)piperazine (m-CPP) in human plasma. Trazodone is a second-generation antidepressant with serotonin antagonist activity. The metabolite seems to be involved in the onset of some side effects of trazodone therapy, thus its determination is very important during therapeutic drug monitoring. Separation was achieved using a C8 reversed-phase column and a mobile phase composed of aqueous phosphate buffer (70%), containing triethylamine, at pH 3.5 and acetonitrile (30%). The UV detector was set at 255 nm and loxapine was used as the internal standard. An original pre-treatment procedure of plasma samples was developed, based on solid-phase extraction with C8 reversed phase cartridges (50mg, 1 mL). The obtained extraction yields values were higher than 90% and precision, expressed as R.S.D., was lower than 5.6%. The method was successfully applied to plasma samples from depressed patients undergoing therapy with trazodone; accuracy results were satisfactory (recovery >91%). Thus, the method seems to be suitable for the therapeutic drug monitoring of trazodone and its main active metabolite in depressed patients' plasma.