Background: Trials studying Motivational Interviewing (MI) to improve medication adherence in patients with schizophrenia showed mixed results. Moreover, it is unknown which active MI-ingredients are associated with mechanisms of change in patients with schizophrenia. To enhance the effect of MI for patients with schizophrenia, we studied MI's active ingredients and its working mechanisms. Methods: First, based on MI literature, we developed a model of potential active ingredients and mechanisms of change of MI in patients with schizophrenia. We used this model in a qualitative multiple case study to analyze the application of the active ingredients and the occurrence of mechanisms of change. We studied the cases of fourteen patients with schizophrenia who participated in a study on the effect of MI on medication adherence. Second, we used the Generalized Sequential Querier (GSEQ 5.1) to perform a sequential analysis of the MI-conversations aiming to assess the transitional probabilities between therapist use of MI-techniques and subsequent patient reactions in terms of change talk and sustain talk. Results: We found the therapist factor “a trusting relationship and empathy” important to enable sufficient depth in the conversation to allow for the opportunity of triggering mechanisms of change. The most important conversational techniques we observed that shape the hypothesized active ingredients are reflections and questions addressing medication adherent behavior or intentions, which approximately 70% of the time was followed by “patient change talk”. Surprisingly, sequential MI-consistent therapist behavior like “affirmation” and “emphasizing control” was only about 6% of the time followed by patient change talk. If the active ingredients were embedded in more comprehensive MI-strategies they had more impact on the mechanisms of change. Conclusions: Mechanisms of change mostly occurred after an interaction of active ingredients contributed by both therapist and patient. Our model of active ingredients and mechanisms of change enabled us to see “MI at work” in the MI-sessions under study, and this model may help practitioners to shape their MI-strategies to a potentially more effective MI.