Background: For patients with coronary artery disease (CAD), smoking is an important risk factor for the recurrence of a cardiovascular event. Motivational interviewing (MI) may increase the motivation of the smokers to stop smoking. Data on MI for smoking cessation in patients with CAD are limited, and the active ingredients and working mechanisms of MI in smoking cessation are largely unknown. Therefore, this study was designed to explore active ingredients and working mechanisms of MI for smoking cessation in smokers with CAD, shortly after a cardiovascular event. Methods: We conducted a qualitative multiple case study of 24 patients with CAD who participated in a randomized trial on lifestyle change. One hundred and nine audio-recorded MI sessions were coded with a combination of the sequential code for observing process exchanges (SCOPE) and the motivational interviewing skill code (MISC). The analysis of the cases consisted of three phases: single case analysis, cross-case analysis, and cross-case synthesis. In a quantitative sequential analysis, we calculated the transition probabilities between the use of MI techniques by the coaches and the subsequent patient statements concerning smoking cessation. Results: In 12 cases, we observed ingredients that appeared to activate the mechanisms of change. Active ingredients were compositions of behaviors of the coaches (e.g., supporting self-efficacy and supporting autonomy) and patient reactions (e.g., in-depth self-exploration and change talk), interacting over large parts of an MI session. The composition of active ingredients differed among cases, as the patient process and the MI-coaching strategy differed. Particularly, change talk and self-efficacy appeared to stimulate the mechanisms of change “arguing oneself into change” and “increasing self-efficacy/confidence.” Conclusion: Harnessing active ingredients that target the mechanisms of change “increasing self-efficacy” and “arguing oneself into change” is a good MI strategy for smoking cessation, because it addresses the ambivalence of a patient toward his/her ability to quit, while, after the actual cessation, maintaining the feeling of urgency to persist in not smoking in the patient.