As a result of enrollment expansion, increasing numbers of students are entering into medical school in China. This combined with a shortage of teachers, means that the learning environment typically consists of a large classroom setting with traditional lecture-based learning (LBL) as the major mode to teaching and learning. In this article, we investigate the preferences for hybrid problem-based learning (hybrid-PBL) or LBL in a large classroom setting. Two hundred five second-year undergraduate students in Third Military Medical University were randomly divided to two groups. The hybrid-PBL group contained 101 students and was taught by hybrid LBL (60%) and tutor-less PBL(40%) in a large classroom. The LBL group consisted of 104 students and was taught by LBL in a large classroom too. Post-teaching performance was assessed by multiple choice questions, short-essay questions, and case-analysis questions, while the students' teaching preferences and satisfaction were assessed by questionnaires. Analysis of the results of both groups in the examination of biochemistry revealed significantly higher scores on short-essay questions and case-analysis questions in the hybrid-PBL group. Students considered hybrid-PBL to be an effective learning method and favored it over the lecture format. Furthermore, students reported positive effects of hybrid-PBL in terms of additional learning resources, critical thinking, and fun learning experiences. These results suggest that hybrid-PBL is better than the traditional LBL method at improving students' basic knowledge and problem-solving skills. Students preferred hybrid-PBL and were satisfied with it. The tutor-less PBL pattern in a large classroom setting may be feasible in Chinese medical schools. (Contains 5 figures, 3 tables, and 1 footnote.)