Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals in both development and postmarketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the quantitative structure-activity relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity, and balanced (40/60) active/inactive ratios were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external data sets. Models with high sensitivity (>73%) and specificity (>94%) for the prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico, and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in preclinical screening of drug candidates for potential hepatotoxicity in humans.