Background MRI follow‐up is widely used for longitudinal assessment of astrocytoma, yet reading can be tedious and error‐prone, in particular when changes are subtle. Purpose/Hypothesis To determine the effect of automated, color‐coded coregistration (AC) of fluid attenuated inversion recovery (FLAIR) sequences on diagnostic accuracy, certainty, and reading time compared to conventional follow‐up MRI assessment of astrocytoma patients. Study Type Retrospective. Population In all, 41 patients with neuropathologically confirmed astrocytoma. Field Strength/Sequence 1.0–3.0T/FLAIR Assessment The presence or absence of tumor progression was determined based on FLAIR sequences, contrast‐enhanced T1 sequences, and clinical data. Three radiologists assessed 47 MRI study pairs in a conventional reading (CR) and in a second reading supported by AC after 6 weeks. Readers determined the presence/absence of tumor progression and indicated diagnostic certainty on a 5‐point Likert scale. Reading time was recorded by an independent assessor. Statistical Tests The Wilcoxon test was used to assess reading time and diagnostic certainty. Differences in diagnostic accuracy, sensitivity, and specificity were analyzed with the McNemar mid‐p test. Results Readers attained significantly higher overall sensitivity (0.86 vs. 0.75; P < 0.05) and diagnostic accuracy (0.84 vs. 0.73; P < 0.05) for detection of progressive nonenhancing tumor burden when using AC compared to CR. There was a strong trend towards higher specificity within the AC‐augmented reading, yet without statistical significance (0.83 vs. 0.71; P = 0.08). Sensitivity for unequivocal disease progression was similarly high in both approaches (AC: 0.94, CR: 0.92), while for marginal disease progressions, it was significantly higher in AC (AC: 0.78, CR: 0.58; P < 0.05). Reading time including application loading time was comparable (AC: 38.1 ± 16.8 sec, CR: 36.0 ± 18.9 s; P = 0.25). Data Conclusion Compared to CR, AC improves comparison of FLAIR signal hyperintensity at MRI follow‐up of astrocytoma patients, allowing for a significantly higher diagnostic accuracy, particularly for subtle disease progression at a comparable reading time. Evidence Level 3 Technical Efficacy Stage 6 J. Magn. Reson. Imaging 2020;52:1197–1206.