Background: It is critical that medical students develop self-directed, lifelong learning skills to navigate medical school successfully and to become competent healthcare professionals. Moreover, the Liaison Committee on Medical Education (LCME), the USA medical school accrediting body, requires activities designed to help students develop self-directed learning (SDL) skills in the preclinical years. Objective: We evaluated the feasibility and effectiveness of a self-directed learning activity in a 6-week first-year medical student course. Design: The course director assigned infectious disease case studies to teams of first-year medical students who individually assessed their knowledge gaps of the case, identified scholarly sources to fill their knowledge gaps, shared the information with their teammates, and reflected on their ability to guide their own learning. Students were asked to rate workload, team effort, acquisition of new clinical knowledge, and lifelong learning skills. Students were also asked to reflect on how this assignment affected their perception of their SDL skills. Descriptive statistics were used to analyze responses to the Likert scale questions. Thematic analysis was applied to the comments. Results: Survey response rate was 80% (131/163). Students strongly or moderately agreed that 1) they spent an appropriate amount of time on the project (94%), 2) the workload was evenly distributed among their teammates (95%), 3) their teammates made significant and timely contributions to the project (97%), 4) the project contributed to learning new clinical knowledge (92%), and 5) the project contributed to the acquisition of lifelong learning skills (85%). The analysis team identified four themes from student reflections on their perception of their self-directed learning skills: self-learning skills, collaboration, application, and metacognition, Conclusions: Study results demonstrated that we successfully implemented a case-based SDL activity in a first-year medical school course and that students perceived the activity as a valuable learning experience.