Human breath can be a complex mixture of trace gases in humid air, with the addition of various anesthetizing agents it becomes even more complex and can present a challenge for the accurate quantification of components. The purpose of this paper was to investigate the quantification of H 2 S as a function of several potential matrix/interference compounds using negative-ion atmospheric pressure chemical ionization with mass spectrometric detection. Analysis was performed by humidifying zero-air and adding various compounds that would be encountered in a perioperative situation. Nitrous oxide, carbon dioxide and to a lesser extent humidity have significant effects on the instrument response to hydrogen sulfide concentration, while halogenated species were found to have little if any complicating effect. It was found that H 2 S can be accurately quantified by using either [SO 3 ] − or [SO 2 ] − /[SO 3 ] − , both of which eliminate the response variability due to interferences.