PURPOSE: To evaluate the variability of quantitative measurements of metastatic liver lesions by using a multi-radiation-dose-level and multi-reader comparison. METHODS: Twenty-three study subjects (mean age, 60 years) with 39 liver lesions who underwent a single-energy dual-source contrast-enhanced staging CT between June 2015 and December 2015 were included. CT data were reconstructed with seven different radiation dose levels (ranging from 25 to 100%) on the basis of a single CT acquisition. Four radiologists independently performed manual tumor measurements and two radiologists performed semi-automated tumor measurements. Interobserver, intraobserver, and interdose sources of variability for longest diameter and volumetric measurements were estimated and compared using Wilcoxon rank-sum tests and intraclass correlation coefficients. RESULTS: Inter- and intraobserver variabilities for manual measurements of the longest diameter were higher compared to semi-automated measurements (p < 0.001 for overall). Inter- and intraobserver variabilities of volume measurements were higher compared to the longest diameter measurement (p < 0.001 for overall). Quantitative measurements were statistically different at < 50% radiation dose levels for semi-automated measurements of the longest diameter, and at 25% radiation dose level for volumetric measurements. The variability related to radiation dose was not significantly different from the inter- and intraobserver variability for the measurements of the longest diameter. CONCLUSION: The variability related to radiation dose is comparable to the inter- and intraobserver variability for measurements of the longest diameter. Caution should be warranted in reducing radiation dose level below 50% of a conventional CT protocol due to the potentially detrimental impact on the assessment of lesion response in the liver.