In previous studies the origin of the majority of isolated sixth nerve palsies was not clear or was ascribed to vascular disease. Our purpose was determine how frequently a causative lesion was demonstrated on MRI in patients with an acute unilateral sixth nerve palsy. We performed a prospective study of 43 patients using a standardised protocol. In 27 patients (63%) a lesion was identified on the initial MRI relevant to the sixth nerve palsy; 21 (49%) were found to have a tumour or tumour-like lesion; the frequency of presumed vasculopathy in this group was 15%. There were 16 patients (37%) with an initially normal MRI, of whom 10 (62%) had a history of vasculopathy, a significantly different proportion from the group of patients with a visible causative lesion. MRI after 3-6 months was normal in all patients with a normal initial MRI. We suggest that MRI should routinely be performed in patients presenting with an acute sixth nerve palsy, even those with evidence of a vasculopathy. If the symptoms regress spontaneously and there is a history of vasculopathy, follow-up MRI is not necessary.