Presented here is a simple approach to the application of HPLC/CE for the separation of complex mixtures. A two-dimensional HPLC/CE instrumental setup was assembled from commercially available equipment. Fractions of the effluent from the HPLC system are collected into microtiter plates with the aid of a microfraction collector which allows the collection of samples by time, drops, or external signal (peaks). The fractions are then dried under vacuum at room temperature in a special unit, reconstituted, and analyzed by CZE. Any size or type of HPLC or CE column can be used with no limitation on the amount of sample injected into the HPLC. Any CE detection procedure, such as LIF, MS, UV, or other, can be used. This setup is practical, simple, robust, and allows the separation of complex mixtures. Preliminary results show the utility of this system for the analysis of a mixture of two protein digests, cytochrome C and myoglobin.