Abstract Objective The A6702 multisite trial confirmed that apparent diffusion coefficient (ADC) measures can improve breast MRI accuracy and reduce unnecessary biopsies, but also found that technical issues rendered many lesions non-evaluable on diffusion-weighted imaging (DWI). This secondary analysis investigated factors affecting lesion evaluability and impact on diagnostic performance. Methods The A6702 protocol was IRB-approved at 10 institutions; participants provided informed consent. In total, 103 women with 142 MRI-detected breast lesions (BI-RADS assessment category 3, 4, or 5) completed the study. DWI was acquired at 1.5T and 3T using a four b-value, echo-planar imaging sequence. Scans were reviewed for multiple quality factors (artifacts, signal-to-noise, misregistration, and fat suppression); lesions were considered non-evaluable if there was low confidence in ADC measurement. Associations of lesion evaluability with imaging and lesion characteristics were determined. Areas under the receiver operating characteristic curves (AUCs) were compared using bootstrapping. Results Thirty percent (42/142) of lesions were non-evaluable on DWI; 23% (32/142) with image quality issues, 7% (10/142) with conspicuity and/or localization issues. Misregistration was the only factor associated with non-evaluability (P = 0.001). Smaller (≤10 mm) lesions were more commonly non-evaluable than larger lesions (p <0.03), though not significant after multiplicity correction. The AUC for differentiating benign and malignant lesions increased after excluding non-evaluable lesions, from 0.61 (95% CI: 0.50–0.71) to 0.75 (95% CI: 0.65–0.84). Conclusion Image quality remains a technical challenge in breast DWI, particularly for smaller lesions. Protocol optimization and advanced acquisition and post-processing techniques would help to improve clinical utility.