Purpose: To compare three region-of-interest (ROI) settings in the assessment of ADC in a clinical trial, and to evaluate the effectiveness of ADC in assessing therapy-induced changes and predicting clinical outcomes. Methods: In a 52-week clinical trial involving patients with axial spondyloarthritis, mean sacroiliac joint (SIJ) ADC measurements using structured, lesion-based, and index-lesion ROI-settings were assessed at baseline and weeks 4, 16, and 52. Variation among the three ROI-settings, correlations with Spondyloarthritis Research Consortium of Canada (SPARCC)-bone marrow edema (BME) SIJ inflammation indices, standardized response means (SRMs), and effectiveness in predicting clinical outcomes were analyzed. Results: Forty of the 53 patients had at least one assessable SIJ lesion on ADC at baseline. The mean of the structured ROI ADC (ADC_struc) was 230 μmm²/s (standard deviation [SD] = 120). This was significantly lower (p < 0.01) than the means of the lesion-based ROI ADC (ADC_lesion = 420 μmm²/s, SD = 210) and index-lesion ROI ADC (ADC_index = 471 μmm²/s, SD = 278), which did not differ. ADC correlated with SPARCC-BME scores at baseline (p < 0.01) as did changes over time in ADC- and SPARCC-BME (p<0.05). At all follow-up time points, responsiveness was high for ADC_lesion (SRM > 0.92) and ADC_index (SRM > 0.87) while moderate for ADC_struc (SRM:0.54-0.67). Baseline ADC and changes in ADC did not predict clinical outcomes. Conclusions: Lesion-based and index-lesion ROI ADC could both be used to evaluate the effectiveness of tumor necrosis factor inhibitor therapy. None of the methods could predict clinical outcomes.