Localized regions of left-right image intensity asymmetry (LRIA) were incidentally observed on T -weighted (T -w) and T -weighted (T -w) diagnostic magnetic resonance imaging (MRI) images. Suspicion of herpes encephalitis resulted in unnecessary follow-up imaging. A nonbiological imaging artifact that can lead to diagnostic uncertainty was identified. To investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty. A retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base. One thousand seven hundred fifty-three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included. 3T. T -w three-dimensional inversion-recovery spoiled gradient-echo (IR-SPGR) or magnetization-prepared rapid gradient-echo (MP-RAGE) and T -w fluid-attenuated inversion recovery (FLAIR) long tau fast spin echo inversion recovery (LT-FSE-IR). Only General Electric, Philips, and Siemens' product sequences were used. LRIA was calculated as the left-right percent difference with respect to the mean intensity from automated anatomical atlas segmented regions. Three neuroradiologists with 37 (**), 32 (**), and 3 (**) years of experience rated the clinical impact of 30 T -w three-dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T m and original T -w images were made. For each image type, a linear mixed effects model was fit using LRIA scores from all scanners, regions, and participants as the outcome and age and sex as predictors. Statistical significance was defined as having a P-value <0.05. LRIA scores were significantly different from zero on most scanners. All clinicians were uncertain or recommended definite diagnostic follow-up in 62.5% of cases with LRIA >10%. Individuals with acute brain pathology or focal neurologic deficits are not enrolled in ADNI; therefore, focal signal abnormalities were considered false positives. LRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR-SPGR, MP-RAGE, and LT-FSE-IR product sequences. 2 Technical Efficacy Stage: 3.