This study aims to compare the effectiveness of Hybrid and Pure problem-based learning (PBL) in teaching clinical reasoning skills to medical students. The study sample consisted of 99 medical students participating in a clerkship rotation at the Department of General Medicine, Chiba University Hospital. They were randomly assigned to Hybrid PBL (intervention group, n = 52) or Pure PBL group (control group, n = 47). The quantitative outcomes were measured with the students’ perceived competence in PBL, satisfaction with sessions, and self-evaluation of competency in clinical reasoning. The qualitative component consisted of a content analysis on the benefits of learning clinical reasoning using Hybrid PBL. There was no significant difference between intervention and control groups in the five students’ perceived competence and satisfaction with sessions. In two-way repeated measure analysis of variance, self-evaluation of competency in clinical reasoning was significantly improved in the intervention group in "recalling appropriate differential diagnosis from patient’s chief complaint" (F(1,97) = 5.295, p = 0.024) and "practicing the appropriate clinical reasoning process" (F(1,97) = 4.016, p = 0.038). According to multiple comparisons, the scores of "recalling appropriate history, physical examination, and tests on clinical hypothesis generation" (F(1,97) = 6.796, p = 0.011), "verbalizing and reflecting appropriately on own mistakes," (F(1,97) = 4.352, p = 0.040) "selecting keywords from the whole aspect of the patient," (F(1,97) = 5.607, p = 0.020) and "examining the patient while visualizing his/her daily life" (F(1,97) = 7.120, p = 0.009) were significantly higher in the control group. In the content analysis, 13 advantage categories of Hybrid PBL were extracted. In the subcategories, "acquisition of knowledge" was the most frequent subcategory, followed by "leading the discussion," "smooth discussion," "getting feedback," "timely feedback," and "supporting the clinical reasoning process." Hybrid PBL can help acquire practical knowledge and deepen understanding of clinical reasoning, whereas Pure PBL can improve several important skills such as verbalizing and reflecting on one’s own errors and selecting appropriate keywords from the whole aspect of the patient.