BACKGROUND: Benefits from cardiac rehabilitation (CR) programs are evidence-based and widely recognized. Less than 50% of people who participate in hospital-based CR programs maintain an exercise regime for as long as six months after completion. Little is known about interventions making the patients continue to exercise after the hospital-based formal program has ended. Methods to ensure sustained benefits of CR need to be tackled. Exercise periodization is a method typically used in sports training, but the impact of periodized exercise to yield optimal beneficial effects in cardiac patients is unclear. Therefore, the purpose of this trial is to evaluate the effects of a long-term exercise periodization on health-related physical fitness components such as cardiorespiratory endurance, muscular strength, skeletal muscle function, and body composition. METHODS: Fifty patients with coronary artery disease will be recruited among those who underwent the hospital-based CR phase. These patients will be randomized (1:1) into one of the following exercise groups: (1) periodized group; and (2) non-periodized group (exercise prescription based on standard guidelines). There will be four assessment time points: at baseline, and 3, 6, and 12 months after starting the exercise training program. At each time point, maximal and submaximal cardiorespiratory fitness, skeletal muscle deoxygenation dynamics, body composition by dual energy radiographic absorptiometry, functional fitness, maximal isometric and dynamic strength, physical activity, and quality of life will be assessed. This experimental design will last for 48 weeks with a frequency of three times per week for both groups. DISCUSSION: Most medium- to long-term exercise-based CR programs do not employ periodization or exercise progression. Randomized controlled trials are necessary to evaluate long-term periodization outcomes and assess the length of change observed in supervised CR programs. This study will contribute to generate evidence-based exercise prescription approaches to prolong the exercise training after the end of hospital-based CR programs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03335319 . Registered on 22 October 2017.