A novel preconcentration/separation approach, which online combined CZE with CD-modified MEKC, was developed for simultaneous enhancing resolving power and detection sensitivity. CZE with cation-selective exhaustive injection and transient ITP preconcentration was used as the first dimension, from which the effluent fractions were further analyzed by CD-modified MEKC acting as the second dimension. As the key to successful integration of CZE with MEKC, a new interface was designed and electro-accumulation focusing strategy was employed to avoid analyte band diffusion at the interface. The comprehensive 2-D system was successfully established with only one high voltage and four electrodes. The grouping of two orthogonal separation techniques, together with analytes preconcentration techniques, significantly enhanced resolution and sensitivity for 2-D separation of cationic compounds. The resulting electro-phoregram was quite different from that of either single CZE or MEKC. Up to 14000- to 35000-fold improvement in sensitivity was obtained relative to conventional electro-kinetic injection method. The limits of detection (S/N= 3) were in the range of 0.03-0.1 mu g/L. The number of theoretical plates was in the range of 103000-184000. This method was successfully applied to the analysis of trace cationic cardiovascular drugs in wastewater.