Direct UV matrix-assisted laser desorption/ionization (MALDI) mass spectrometric analysis of uncomplexed, underivatized, highly sulfated oligosaccharides has been carried out using ionic liquids as matrices. Under conventionally used MALDI time-of-flight experimental conditions, uncomplexed polysulfated oligosaccharides do not produce any signal. We report that 1-methylimidazolium alpha-cyano-4-hydroxycinnamate and butylammonium 2,5-dihydroxybenzoate ionic liquid matrices allow the detection of picomole amounts of the sodium salts of a disaccharide, sucrose octasulfate, and an octasulfated pentasaccharide, Arixtra. The experimental results indicate that both analytes undergo some degree of thermal fragmentation with a mass loss corresponding to cleavage of O-SO3Na bonds in the matrix upon laser irradiation, reflecting lability of sulfo groups.