We report a chemical-vapor-assisted electrospray ionization (ESI) technique to improve the detection sensitivity of ESI mass spectrometry (MS). This simple technique involves introducing a chemical vapor into the sheath gas around the nano-ESI spray tip or through a tubing with its outlet placed close to the spray tip. A variety of chemical vapors were tested and found to have varying degrees of effects on analyte signal intensities. The use of benzyl alcohol vapors in ESI was found to increase signal intensities of standard peptides by up to 4-fold. When this technique was combined with capillary liquid chromatography tandem MS (LC-MS/MS), the number of unique peptides identified in the acid hydrolysate of alpha casein increased by 45% and the number of peptides and proteins identified in a tryptic digest of E. coli cell lysate increased by 13% and 14%, respectively, along with an increased average match score. This technique could also increase the analyte signals for some small molecules, such as phenylephrine, by up to 3-fold. The increased analyte signals observed in the chemical-vapor-assisted ESI process is related to the enhancement of the ionization efficiency in ESI. The method can be readily implemented to an existing ESI mass spectrometer at minimum cost for improving detection sensitivity.