An MEKC method was developed in order to separate a cold medicine formulation containing acetaminophen, ephedrine sulfate, doxylamine succinate, and dextromethorphan hydrobromide as active pharmaceutical ingredients. Because of their similar physical and chemical properties, it was a challenge to separate the basic compounds without sample pretreatment. In addition, the high content of alcohol and sucrose together with the variety of further excipients had to be considered. Thus, the complex matrix required several optimization steps. These included the search for the optimum pH and for a suitable sodium dodecyl sulfate concentration to avoid matrix-capillary wall interaction and to ensure precision. As a second developing step, an internal standard (benzocaine) was chosen to guarantee a high level of quantitative performance. An RSD% value of the peak areas between 1.0 and 2.0 was reached. The employed method development strategy can be generalized to similar separation approaches in the future.