For the study, researchers sought to understand that Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions as compared to normal imaging. It was unknown if the capacity to predict how soon a disease might worsen was improved by the presence of predominantly peripheral lesions (PPLs). To determine if PPLs identified on UWF imaging were associated with a higher risk of disease progression than that which was associated with the baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. This cohort trial, a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites from February to December 2015, involved 388 participants. At the beginning of the study, 200° UWF-color images were collected, and throughout the following 4 years, they were analyzed for DRSS. It was examined whether PPL was present in the baseline UWF-color and UWF-fluorescein angiography (FA) photos. Data from May 2020 to June 2022 were analyzed. Treatment of diabetic macular edema or DR was at the discretion of the investigator. When defining primarily peripheral lesions as DR lesions having a higher extent outside of the fields, the 7 standard ETDRS fields were utilized as a point of reference. Receiving DR treatment or worsening by at least 2 steps on the DRSS was considered the major outcome for the disease getting worse. While performing the study, the participant’s 2 study eyes’ correlation and the DRSS baseline score were taken into consideration. Data for 544 study eyes with nonproliferative DR (NPDR)—182 participants (50%) women; median age, 62 years; and 68% White—were analyzed. For eyes with mild baseline NPDR, the rates of disease progression over 4 years were 45%, for those with moderate baseline NPDR, 40%, for those with moderately severe baseline NPDR, 23%, and for those with severe baseline NPDR, 43%. However, compared to baseline colour PPL (present vs absent: 38% vs 43%; present vs absent: HR, 0.78; 95% CI, 0.57-1.08; P=.13), disease worsening was connected to FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36;P<.001). The existence of FA PPL was associated with a higher likelihood of disease advancement regardless of the initial DRSS score, even though there was no linkage between color PPL and disease progression during a 4-year period. According to these results, it may be simpler to forecast when the diseases in NPDR eyes will worsen by employing UWF-FA to evaluate the retinas outside of the conventional ETDRS areas. These findings supported the use of UWF-FA in clinical treatment and DR staging systems moving forward, enabling a more accurate prognosis evaluation in NPDR eyes.