A novel method with quaternary ammonium salts as internal additives has been applied to the mass-scale calibration of time-of-flight secondary ion mass spectrometry (TOF-SIMS). Five kinds of quaternary ammonium salts, octyltrimethylammonium bromide (C8TMA), tetradecyltrimethylammonium chloride (C14TMA), octadecyltrimethylammonium chloride (C18TMA), cetylpyridinium chloride (CPC) and benzyldimethyltetradecylammonium chloride (Bzl) were diluted with NH3 aqueous solution and were mixed in equal quantities. The mixed solution was covered on a Si wafer and was measured by TOF-SIMS. When molecular ions of C8TMA, C14TMA, and C18TMA were used for the mass-scale calibration, the relative mass accuracy of low-mass CXHY fragment ions indicated negative values and depended on the carbon chain length and the degree of unsaturation. This result means that the conventional mass-scale calibration with frequently employed low-mass CXHY fragment ions leads to degradation of the mass accuracy of high-mass molecular ions. To improve the mass accuracy of molecular ions of CPC and Bzl, ions should be selected for the mass-scale calibration in the following two ways: One way is for ions to consist only of molecular ions of C8TMA, C14TMA, and C18TMA, and the other way is for ions to include one of the molecular ions: C8TMA, C14TMA, and C18TMA, along with the CXHY fragment ions. This novel mass-scale calibration method is promising for realizing the correct identification of unknown high-mass molecular ions. Those quaternary ammonium salts are powerful candidates of internal additives. Copyright © 2014 John Wiley & Sons, Ltd.