Purpose To assess the utility of a machine-learning approach for predicting liver function based on technetium-99 m-galactosyl serum albumin (Tc-99m-GSA) single photon emission computed tomography (SPECT)/CT. Methods One hundred twenty-eight patients underwent a Tc-99m-GSA SPECT/CT-based liver function evaluation. All were classified into the low liver-damage or high liver-damage group. Four clinical (age, sex, background liver disease and histological type) and 8 quantitative Tc-99m-GSA SPECT/CT features (receptor index [LHL15], clearance index [HH15], liver-SUVmax, liver-SUVmean, heart-SUVmax, metabolic volume of liver [MVL], total lesion GSA [TL-GSA, liver-SUVmean x MVL] and SUVmax ratio [liver-SUVmax/heart-SUVmax]) were obtained. To predict high liver damage, a machine learning classification with features selection based on Gini impurity and principal component analysis (PCA) were performed using a support vector machine and a random forest (RF) with a five-fold cross-validation scheme. To overcome imbalanced data, stratified sampling was used. The ability to predict high liver damage was evaluated using a receiver operating characteristic (ROC) curve analysis. Results Four indices (LHL15, HH15, heart SUVmax and SUVmax ratio) yielded high areas under the ROC curves (AUCs) for predicting high liver damage (range: 0.89-0.93). In a machine learning classification, the RF with selected features (heart SUVmax, SUVmax ratio, LHL15, HH15, and background liver disease) and PCA model yielded the best performance for predicting high liver damage (AUC = 0.956, sensitivity = 96.3%, specificity = 90.0%, accuracy = 91.4%). Conclusion A machine-learning approach based on clinical and quantitative Tc-99m-GSA SPECT/CT parameters might be useful for predicting liver function.