Multifunctional genes are important genes because of their essential roles in human cells. Studying and analyzing multifunctional genes can help understand disease mechanisms and drug discovery. We propose a computational method for scoring gene multifunctionality based on functional annotations of the target gene from the Gene Ontology. The method is based on identifying pairs of GO annotations that represent semantically different biological functions and any gene annotated with two annotations from one pair is considered multifunctional. The proposed method can be employed to identify multifunctional genes in the entire human genome using solely the GO annotations. We evaluated the proposed method in scoring multifunctionality of all human genes using four criteria: gene-disease associations; protein–protein interactions; gene studies with PubMed publications; and published known multifunctional gene sets. The evaluation results confirm the validity and reliability of the proposed method for identifying multifunctional human genes. The results across all four evaluation criteria were statistically significant in determining multifunctionality. For example, the method confirmed that multifunctional genes tend to be associated with diseases more than other genes, with significance [Formula: see text]. Moreover, consistent with all previous studies, proteins encoded by multifunctional genes, based on our method, are involved in protein–protein interactions significantly more ([Formula: see text]) than other proteins.