Participant engagement in structured lifestyle change programs (LCPs) is essential for adopting behaviors that promote weight loss; however, the challenges to, and facilitators that promote, engagement with such programs are not well understood. We conducted a mixed-methods study among real-world LCP participants to assess factors associated with program engagement and to examine the reasons for withdrawal. Using electronic health records (EHR), we identified LCP eligible participants between 2010 and 2017. Multivariable logistic regression was used to assess associations between program engagement and baseline characteristics. Semi-structured interviews with LCP participants were conducted and thematically analyzed to examine reasons for withdrawal. A total of 1,813 LCP participants were included. The median number of sessions attended was 10 of 21-25 sessions. Highest LCP engagement was associated with factors potentially related to self-efficacy/motivation, such as older age, higher baseline weight, prior healthcare utilization and an absence of a history of smoking or depression. Engagement was also negatively associated with being Non-Hispanic Black versus White. The qualitative analysis of the interviews revealed four general themes pertaining to participants' withdrawal: competing priorities, perceived program effectiveness, characteristics of the program, and facilitator-related factors. Taken together, results from this mixed-methods study suggest that motivation and self-efficacy are important for program engagement; future LCP enhancements should incorporate flexible formats that may help participants manage competing priorities and maximize personal and cultural relevance for all racial/ethnic groups, especially those who have not benefitted fully. Furthermore, participants should be encouraged to set realistic goals to manage expectations.