This study aimed to observe the efficacy of 4-2-1 principle-guided Pan-Retinal Photocoagulation (PRP) for treating severe Non-Proliferative Diabetic Retinopathy (NPDR). This multi-center, prospective, and non-comparative clinical study involved performance of PRP in 43 patients (43 eyes) with severe NPDR, who were diagnosed according to 4-2-1 principles, and were followed up for 6 months. Best corrected visual acuity (BCVA) tests, Colored Fundus Photography (CFP), and Fluorescence Fundus Angiography (FFA) were performed before and after PRP. Assessments were again performed in the 6-month followup to evaluate efficacy. The mean BCVAs before and after PRP were 59.91 ± 14.58 and 62.86 ± 15.41 letters, respectively (t=1.782, P>0.05). Thirty-nine eyes exhibited effective BCVA results (90.7%), 38 eyes exhibited effective CFP results (88.4%), and 36 eyes exhibited effective FFA results (83.72%); no statistically significant difference was found (χ2=0.19, P>0.05). Thus, 4-2-1 principle-guided PRP treatment was an effective approach in the absence of FFA. Using this approach, disease progression could be effectively controlled in the vast majority of patients with severe NPDR, preventing severe visual impairment.