Localised retinal nerve fibre layer defects (RNFLDs) are reported to indicate the degree of glaucomatous damage but can also be sequelae of retinal vascular insufficiency as a result of systemic vascular factors. We investigated the association between RNFLDs and cardiovascular risk factors. RNFLDs were detected in 440 (29.2%) of 1508 subjects. The presence of RNFLDs was associated with higher HbA1c (odds ratio [OR] 1.289, p < 0.001), higher 24-h mean systolic blood pressure (SBP; OR 1.013, p < 0.005), and lower estimated glomerular filtration rate (eGFR; OR 0.995, p < 0.005). An increasing number of RNFLDs was correlated with higher SBP (r = 0.186, p < 0.001), higher HbA1c (r = 0.128, p < 0.010), lower eGFR (r = -0.112, p < 0.020), and younger age (r = -0.303, p < 0.001). Subjects with RNFLDs had a higher predicted 10-year risk of atherosclerotic cardiovascular disease than did those without RNFLDs (9.7% vs 7.9%, p = 0.008 in middle-aged subjects, 25.6% vs 23.2%, p = 0.040 in older subjects). In conclusion, RNFLDs are associated with SBP, eGFR, and HbA1c. Concomitant cardiovascular risk factors should be considered when evaluating patients with localised RNFLDs.