The role for immediate neuroimaging in patients 50 years of age or older with acute isolated third, fourth, and sixth nerve palsies is controversial. We prospectively evaluated 66 patients, aged 50 years and older (median 67 years, range 50-85), with acute isolated ocular motor mononeuropathies. Our purpose was to evaluate both the role of neuroimaging and the role of clinical assessment in determining etiology. We found that clinical features, including time to maximal diplopic symptoms, were not predictive of etiology (median 2 days to maximal diplopic symptoms for both peripheral microvascular and other etiologies). The presence of any common vascular risk factor, including diabetes mellitus, hypertension, hypercholesterolemia, or coronary artery disease, was significantly associated with peripheral microvascular etiology in this cohort (p=0.0004, Fisher's exact test). Despite the high prevalence of peripheral microvascular ischemia as an etiology in this age group, other causes were identified by magnetic resonance imaging (MRI) or computed tomography (CT) scanning in 14% of patients. Diagnoses included brainstem and skull base neoplasms, brainstem infarcts, aneurysms, demyelinating disease, and pituitary apoplexy. Neuroimaging procedures may have a role in the initial evaluation of patients 50 years of age or older with acute ocular motor mononeuropathies.