To retrospectively review the efficacy of intermittent fasting 5:2 plus program (30% of energy requirements on fast days and 70% of energy requirements on nonfasting days) in Chinese patients with overweight or obesity. This retrospective cohort study evaluated weight loss outcomes of patients treated with 12 weeks weight loss program in clinic. Adults with overweight or obesity participated in intermittent fasting 5:2 plus, daily calorie restriction (70% of energy requirements every day) or daily calorie restriction with meal replacement (70% of energy requirements every day, partly provided with high-protein meal replacement) programs for 12 weeks. The primary objective was to compare the weight loss of three groups. The primary outcome measure was the change in the % total weight loss. A total of 131 patients (35.3 ± 10.1 years; 81.7% female) were included, and the mean weight loss was 7.8 ± 4.4% after 12 weeks. The intermittent fasting 5:2 plus group (n = 42) achieved 9.0 ± 5.3% weight loss, compared with 5.7 ± 3.7% in the daily calorie restriction group (n = 41) (p < 0.001) and 8.6 ± 3.5% in the meal replacement group (n = 48) (p = 0.650). A total of 85.7% of patients in the intermittent fasting 5:2 plus group lost more than 5% body weight, vs. 58.5% in the daily calorie restriction group (p = 0.008), and 45.2% lost more than 10% body weight, vs. 14.6% in the daily calorie restriction group (p = 0.005). No serious adverse events were reported in the three groups. The intermittent fasting 5:2 plus program more effectively led to weight loss than daily calorie restriction in the short-term in Chinese patients with overweight or obesity. A longer-term prospective randomized controlled trial is needed.