Although human-computer interaction (HCI) has been developing for thirty years, the field has advanced slowly due to a lack of knowledge about HCI structure. This research thus seeks to explore and clarify HCI intellectual structure. Data collected from the ISI Web of Knowledge totaled 1,168 HCI related articles, and 33,724 references were identified. There were 75 highly cited research articles identified using a citation analysis and then implementing co-citation analyses, including factor analysis, multidimensional scaling and cluster analysis. According to cluster analysis, twelve core knowledge domains of HCI were identified: System capability, User interface design, Task of the HCI system, Evaluation of interaction, User acceptance of technology, Personalized system design, Interface analysis, Performance measurement and improvement, Development of interaction, Human reaction to technology, Facial expression, and Effective interaction. Among these topics, two of them, “Personalized system design” and “Facial expression”, are new intellectual cores which did not appear in previous related researches. The findings of this study provide an intellectual structure and research directions for researchers and practitioners interested in the HCI field.