To determine the associations of predominant peripheral lesions (PPLs) with systemic comorbidities in individuals with diabetic retinopathy.This is a multicenter cross-sectional observational study conducted across three tertiary eye care centers in south India between January 2019 and July 2021. Ultra-widefield fundus images of consecutive patients with varying severity of diabetic retinopathy with data on systemic comorbidities were classified based on the presence or absence of PPL. Systemic comorbidities (hypertension, diabetic kidney disease, coronary artery disease, dyslipidemia, and anemia) were compared between the two groups.A total of 879 participants (70.1% males) were included in the study, of which 443 (50.4%) patients had PPL. The mean age of the study participants was 56 ± 10 years, mean age of onset of diabetes was 41.24 ± 11.6 years, and mean duration of diabetes was 15.39 ± 7.6 years. The number of PPL increased with increasing severity of DR. Of all the systemic comorbidities analyzed, we found that coronary artery disease (CAD) had a significant association with PPL (Odds ratio [OR]-1.69; 95% confidence interval [CI], 1.12-2.55; P = 0.013) after adjusting for diabetic retinopathy severity, duration of diabetes, and age of onset of diabetes.The presence of PPL is a marker for coronary artery disease and early referral to cardiology is warranted.