To the best of our knowledge, this is the first systematic LOQ comparison of a broad chemical space including xenobiotics from multiple exposure sources. Despite our efforts to ensure a high degree of comparison, inherent technical discrepancies remained because high-and low-resolution instruments are based on fundamentally different measurement principles. QQQ focuses on the reliable quantitation of a pre-defined target list, whereas HRMS specializes in the non-targeted discovery of molecules. Different acquisition modes were used (multiple reaction monitoring vs. full MS scan) that imposed restrictions on the direct comparison of the generated data. Both instruments, however, were used in the measurement mode typically used in exposomic or metabolomic applications. The tailored LC-MS/MS assay was operated in reaction monitoring and could even detect extremely low concentrations in the ppt range but was restricted to the predetermined list of analytes. As showcased by the suspect screening of the urine samples, untargeted HRMS analyses within a specified mass range (full scan mode) enabled the detection of all chemicals in the chosen m/z window and the subsequent discovery of unexpected and unknown molecules. However, exposure to analytes at low levels is often not quantifiable in HRMS. In addition, the specific instruments and methods used in the comparison may impact the outcome. This study included two LC-MS configurations from leading vendors in the respective field. Therefore, e.g., the ESI source design was different and this aspect may influence instrument sensitivity. The LC systems' void volumes were also not identical; nevertheless, the remarkable similarity in retention time (average shift = 11 s) indicated that only minor variations originated from the chromatographic separation. The same sample preparation was applied for both approaches to focus on differences coming from the instrumentation only. However, the sample preparation might be adapted for HRMS and QQQ measurements, respectively. Matrix effects for example are significantly affected by the sample preparation affecting the yielded LODs.