Background: Precise quantitative tests are not available to measure synthetic liver function prior to major hepatectomy. Most centers rely on imperfect surrogates including laboratory studies and CT volumetry. Indocyanine green clearance can quantify functional hepatocyte mass, but does not provide regional assessment and has not been widely adopted in North America. Nuclear medicine tests are rarely used for preoperative planning, but are an additional option to asses overall, hemi-liver, and segmental hepatic function. The purpose of this study was to compare CT volumetry with functional nuclear medicine testing as an accurate measure to predict hepatic function of the future liver remnant. Methods: CT volumetry and functional nuclear medicine data were collected prospectively for patients undergoing evaluation for hepatocellular carcinoma (HCC) from February 2016-May 2018. Paired CT and nuclear medicine scans were obtained within 9 months (median 1 month) of one another. Nuclear medicine scans were performed with freshly prepared technetium 99m labeled mebrofenin (an iminodiacetic analogue), initially dynamic planar images were acquired and thereafter a single-photon emission computed tomography (SPECT) scan was performed. Total and regional liver volumes were calculated and reported by an attending radiologist. Extent of discrepancy between modalities was calculated. Clinical and demographic characteristics including the extent of chronic liver disease were recorded. Results: Over 27 months, 63 patients with HCC underwent both CT and functional nuclear medicine imaging. Median age was 64 years (range 25–85 yrs). Fifty patients (74.6%) were classified as cirrhotic. Of the cirrhotic patients, 60% (n = 30) had Child’s A, 38% Child's B (n = 19) and 2% Child's C cirrhosis (n = 1). Standard CT volumetry overestimated total functional liver volume, TLV, (median 1508 ml; range 570.2–4112.9 ml) when compared with functional nuclear medicine scan (median 1320 ml; range 6.9–3546.1 ml; p = 0.02). Significant discrepancy existed between regional liver volumes and percent contribution to hepatic function. The median volume of the right hemi-liver by CT volumetry was 906 ml (range 187–2324; 61% of TLV) and 721 ml by functional nuclear medicine study (range 12–2050; 65% of TLV; p = 0.03). Less discrepancy was found between left hemi-liver measurements: median volume by CT volumetry was 591 ml (range 100–2236; 38% of TLV) and 512 ml by functional nuclear medicine scan (range 69–2050; 35% of TLV; p = 0.21). Median discrepancy in hemi-liver volumes was 4.8% (range 0.2–51.5%) for the right, and 4.7% (0.2–51.5%) for the left hemi-liver. More than half of the patients (n = 34) had less than 5% discrepancy in hemi-liver volumes, 10 had 5–10% discrepancy, 11 had 10–20% discrepancy. Eight patients (12%) had volume discrepancies greater than 20% between CT volumetry and nuclear medicine imaging. Conclusion: Significant discrepancy exists between standard CT volumetry and nuclear medicine SPECT for estimating functional liver volumes. Compared with functional nuclear medicine imaging, CT volumetry appears to overestimate liver volume. Functional nuclear medicine scans provide additional information and may be a useful and affordable tool for preoperative assessment of the future liver remnant when planning major hepatectomy.