Monitoring of N-nitrosamines in various matrices is of high interest, due to their potential carcinogenicity and detection in a variety of commodities and pharmaceuticals consumed by humans. These impurities require sensitive and selective detection in the sub-ng/mL range. The following method is capable of simultaneous detection and quantitation of six widely analyzed N-nitrosamines (NDMA, NDEA, NMBA, NDBA, NEIPA, and NDIPA) at or less than 0.1 ng/mL, using a highly sensitive and selective QTof acquisition mode. Referred to as Tof MRM, this acquisition mode provides selectivity through isolation of the analyte precursor m/z in the quadrupole, followed by a targeted increase in signal. Presented here are the UPLC chromatographic separation and LLODs, LLOQs, and linearity for the six N-nitrosamines analyzed using the Tof MRM method. Quantitative performance of this method is reported for NDMA and NDEA, demonstrating precise, accurate and repeatable measurement at both 1.25 and 12.5 ng/mL quality control (QC) levels. Furthermore, the use of the UNIFI Scientific Information System for acquisition and data processing offers a modern platform for GxP-compliant HRMS analysis of the investigated N-nitrosamines.