The current trend for increasing technical complexity in the field of CE-ESI-MS interfaces has incited for more accessible alternatives. In this work, a simple low sheath-flow ESI interface operating in the submicroliter nanospray regime without nebulizing gas assistance was evaluated. The use of sheath liquid enabled improving the ionization of the analytes, while the absence of nebulizing gas minimized sample dilution and loss of efficiency. After a rapid qualification, the effect of main operational parameters such as sheath liquid composition and flow rate, working distance and ESI potential was studied. Simulation of the mixing processes inside the Taylor cone proved its size to be of utmost importance in band broadening processes. As a proof of concept, the interface was eventually applied to a set of representative basic drugs analyzed by CE-TOF/MS. Limits of detection reached the 25–100 ppb range with suitable robustness and repeatability results. This design has demonstrated good performance while being simple and accessible to the user.