<div><p>Direct-reading organic vapor monitors are often used to measure volatile organic compound concentrations in complex chemical gas mixtures. However, there is a paucity of data on the impact of multiple gases on monitor performance, even though it is known that monitor sensitivity may vary by chemical. This study investigated the effects of interferents on the performance of the MIRAN SapphIRe Portable Ambient Air Analyzer (SAP) and Century Portable Toxic Vapor Analyzer (TVA-1000) when sampling a specific agent of interest (cyclohexane). The TVA-1000 contained a dual detector: a photoionization detector (PID) and a flame ionization detector (FID). Three devices of each monitor were challenged with different combinations of cyclohexane and potential interferent vapors (hexane, methyl ethyl ketone, trichloroethylene, and toluene) at 21°C and 90% relative humidity (RH), an extreme environmental condition. Five replicates at four target concentrations were tested: 30, 150, 300, and 475 ppm. Multiple proportions of cyclohexane to interferent enabled the determination of the interferent effect on monitor performance. The monitor concentrations were compared to reference concentrations measured using NIOSH Method 1500. Three scenarios were investigated: no response factor, cyclohexane response factor, and weighted-mixed response factor applied. False negatives occurred more frequently for PID (21.1%), followed by FID (4.8%) and SAP (0.2%). Measurements from all monitors generally had a positive bias compared to the reference measurements. Some monitor measurements exceeded twice the reference concentrations: PID (36.8%), SAP (19.8%), and FID (6.3%). Evaluation of the 95% confidence intervals indicated that performance of all monitors varied by concentration. In addition, the performance of the PID and SAP varied by presence of an interfering compound, especially toluene and hexane for the PID and trichloroethylene for the SAP. Variability and bias associated with all these monitors preclude supplanting traditional sorbent-based tube methods for measuring volatile organic compounds (VOCs), especially for compliance monitoring.</p><p>Implications: <i>Industrial hygienists need to use care when using any of the three monitor detection types to measure the concentration of unknown chemical mixtures. Monitor performance is affected by the presence of interferents. Application of manufacturer recommended response factors may not adequately scale measurements to minimize monitor bias when compared to standard reference methods. Users should calibrate their monitors to a known reference method prior to use, if possible. Each of the monitors has its own limitations, which should be considered to ensure quality measurements are reported.</i></p></div