Chemical ionization mass spectrometry (CIMS) techniques have become prominent methods for sampling trace gases of relatively low volatility. Such gases are often referred to as being “sticky”, i.e., having measurement artifacts due to interactions between analyte molecules and instrument walls, given their tendency to interact with wall surfaces via absorption or adsorption processes. These surface interactions can impact the precision, accuracy, and detection limits of the measurements. We introduce a low-pressure ion–molecule reaction (IMR) region primarily built for performing iodide-adduct ionization, though other adduct ionization schemes could be employed. The design goals were to improve upon previous low-pressure IMR versions by reducing impacts of wall interactions at low pressure while maintaining sufficient ion–molecule reaction times. Chamber measurements demonstrate that the IMR delay times (i.e., magnitude of wall interactions) for a range of organic molecules spanning 5 orders of magnitude in volatility are 3 to 10 times lower in the new IMR compared to previous versions. Despite these improvements, wall interactions are still present and need to be understood. To that end, we also introduce a conceptual framework for considering instrument wall interactions and a measurement protocol to accurately capture the time dependence of analyte concentrations. This protocol uses short-duration, high-frequency measurements of the total background (i.e., fast zeros) during ambient measurements as well as during calibration factor determinations. This framework and associated terminology applies to any instrument and ionization technique that samples compounds susceptible to wall interactions.