In ion mobility spectrometry (IMS), reduced mobility (K₀) is an identification parameter of gas-phase ions but, frequently, these values are different whether there is contamination with moisture and other volatile compounds or not. We studied the effect of 2-butanol as a contaminant in IMS using electrospray ionization-IMS-mass spectrometry. The ion mobilities of valinol, phenylalanine, and tryptophan were measured with 0.0, 1.7, 3.4, 5.1, and 6.8 mmol m⁻³ of 2-butanol (0.065, 0.131, 0.196, and 0.261 ppmv, respectively) in the buffer gas at 100, 150, 200, and 250 °C. At 100 °C, K₀ values of valinol, phenylalanine, and tryptophan ions decreased by −14.2%, −11.9%, and −10.3%, respectively, with 6.8 mmol m⁻³ of 2-butanol in the buffer gas. These different changes in mobilities were due to the formation of large 2-butanol : analyte ion clusters. The largest mobility reductions were obtained at 100 °C due to increased 2-butanol : analyte ion interactions, calculated using Gaussian. At 250 °C, the formation of clusters was hindered, and the injection of 2-butanol did not affect mobilities. That the largest mobility changes when contamination was present were obtained at the lowest temperature, as is almost always the case for field IMS instruments, indicates that drift-tube ion mobility measurements must be carried out at high temperatures to obtain reliable reduced mobilities. Contaminants of mass or polarity larger than that of 2-butanol will produce larger mobility changes. These mobility changes will be much larger at the relatively low temperatures used by most field instruments due to a balance between heating power consumption and the benefits of high temperatures. IMS at high temperatures could be the choice for the detection of illegal drugs, explosives, and biological and warfare agents in airports, ports, and customs to avoid false positives, ease the transit of passengers and cargo, increase the seizure of illegal substances, and save money and discomfort due to unnecessary delays produced by false positives.