A compatible buffer system for the coupling of capillary electrophoresis (CE) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was developed. The employed interface consists of a robot to drive a sliver-covered separation capillary and an AnchorChip MALDI-MS target. The outlet of the capillary is grounded and connected to the pre-deposited buffer droplet on the MALDI target to make the electric connection and allow sample crystallization for MALDI-MS. The possibility of using only one buffer already containing the matrix for MALDI-MS for the separation and the ionization was investigated and tested on protein and peptide samples. The results show that the proposed buffer system is suitable for CE-MALDI-MS coupling, simplifies the traditional buffer mixing steps in off-line CE-MALDI-MS protocols, and is therefore highly promising for on-line analysis.