The opioid crisis and emergence of fentanyl, fentanyl analogues, and other synthetic opioids has highlighted the need for sensitive and robust detection for interdiction at screening points, notably vehicles at border crossings and packages at postal facilities. This work investigates the discriminative potential, sensitivity and specificity, of ion mobility spectrometry (IMS) for the detection of fentanyl and fifteen (15) fentanyl-related compounds (analogues, other opioids, and metabolites) relative to confounding environmental interferents. The environmental background interferent levels, frequency and intensity, were derived from over 10 000 screening samples collected from delivery vehicles entering a federal site. A receiver operating characteristic (ROC) curve methodology was employed to quantify the relationship between sensitivity and specificity for these target compounds on two instruments/configurations. These instrument configurations differed in desorption and drift tube temperatures, reactant ion dopant chemistry, and analysis time. This work identified reduced mobility areas of high interference that resulted in increased false positive rates (FPR), effectively reducing sensitivity (true positive rate: TPR) in those regions. Except for a few target compounds on either of the instruments that exhibited elevated FPRs, detection of fentanyl and fentanyl-related species was achieved at single to tens of nanograms with ≥90% TPR and ≤2% FPR. This work established the importance of systematic environmental background characterization at each specific screening setting in evaluating a platform's true performance.