Michler's ethylketone (MEK, 4,4'-bis(diethylamino)benzophenone), commonly-known as an intermediate in the synthesis of dyes and pigments, was successfully screened and optimized as a novel matrix for the enhancement of lipid in situ detection and imaging in tissues by MALDI-MSI. The results show several properties of MEK as a powerful MALDI matrix, including strong UV absorption, µm-sized crystals and uniform matrix-coating, super high vacuum chemical stability, low matrix-related ion interference, super soft ionization, and high lipid ionization efficiency.