Objective. This study is aimed at evaluating the clinical efficacy and safety of innovative phased combination of low-level laser therapy (LLLT) and Photodynamic Therapy (PDT) in treatment of patients with acne based on the immediate and long-term follow-up. Material and Methods. A total of 276 patients aged 16 to 44 years with various forms of acne; most of them had severe manifestations of acne (n = 126, or 45.6%) and duration of the disease of 1 to 5 years (n = 157, 56.9%). Patients were randomized into two groups. Group 1 (study group) included 237 (85.7%) patients with acne, who were administered with phased LLLT and PDT therapy based on a proprietary method. Group 2 (control group) included 39 (14.3%) patients with acne, who received conventional combination therapy. The efficacy of the innovative technology of treatment of patients with acne was assessed based on the follow-up during 1 year (n = 144), 2 years (n = 128), 3 years (n = 128), 4 years, and 5 years (n = 104). The imbalance of cell-mediated and humoral immunity and phagocytosis values that was detected in these patients before treatment is indicative of the development of combined secondary immune deficiency. Results: Dynamic monitoring of clinical and paraclinical parameters in the study and control group patients with acne based on both immediate (1–2 years) and long-term (3-5 years) follow-up showed that the study group patients with acne had one relapse, whereas no patients in the control group had one relapse per year, but 2–3 relapsed of acne were detected. The relapse rate in the control group was 2.3-3.1-fold higher compared to that in the study group (p<0.01). Furthermore, the severity of acne relapses in the control group was equivalent to that in the study group in 42.3% of patients, whereas 57.7% of cases were characterized by substantially and significantly more severe clinical manifestations (p <0.01). Thus, scheduled innovative combination of LLLT and PDT resulted in clinical remission and significant improvement and normalization of the immune status in 96.7% of patients.