Use of silica stationary phase and aqueous-organic mobile phases could significantly enhance LC-MS-MS method sensitivity. The LC conditions were compatible with MS detection. Analytes with basic functional groups were eluted with acidic mobile phases and detected by MS in the positive ion mode. Analytes with acid functional groups were eluted with mobile phases at neutral pH and detected by MS in the negative ion mode. Analytes poorly retained on reversed-phase columns showed good retention on silica columns. Compared with reversed-phase LC-MS-MS, 5-8-fold sensitivity increases were observed for basic polar ionic compounds when using silica columns and aqueous-organic mobile phase. Up to a 20-fold sensitivity increase was observed for acidic polar ionic compounds. Silica columns and aqueous-organic mobile phases were used for assaying nicotine, cotinine, and albuterol in biological fluids.