PURPOSE: To determine the variability of lesion size measurements in computed tomography data sets of patients imaged under a “no change” (“coffee break”) condition and to determine the impact of two reading paradigms on measurement variability. METHOD AND MATERIALS: Using data sets from 32 non-small cell lung cancer patients scanned twice within 15 minutes (“no change”), measurements were performed by five radiologists in two phases: (1) independent reading of each computed tomography dataset (timepoint): (2) a locked, sequential reading of datasets. Readers performed measurements using several sizing methods, including one-dimensional (1D) longest in-slice dimension and 3D semi-automated segmented volume. Change in size was estimated by comparing measurements performed on both timepoints for the same lesion, for each reader and each measurement method. For each reading paradigm, results were pooled across lesions, across readers, and across both readers and lesions, for each measurement method. RESULTS: The mean percent difference (±SD) when pooled across both readers and lesions for 1D and 3D measurements extracted from contours was 2.8 ± 22.2% and 23.4 ± 105.0%, respectively, for the independent reads. For the locked, sequential reads, the mean percent differences (±SD) reduced to 2.52 ± 14.2% and 7.4 ± 44.2% for the 1D and 3D measurements, respectively. CONCLUSION: Even under a “no change” condition between scans, there is variation in lesion size measurements due to repeat scans and variations in reader, lesion, and measurement method. This variation is reduced when using a locked, sequential reading paradigm compared to an independent reading paradigm.