We performed a study to investigate differences and similarities between patients with Sneddon's syndrome and those with primary antiphospholipid syndrome (PAS), by clinical follow-up, magnetic resonance imaging (MRI) and angiography. Nine patients with Sneddon's syndrome and 11 patients with PAS were assessed at diagnosis and followed for a mean of 6 years. The clinical and MRI findings indicated that Sneddon's syndrome and PAS are distinct entities. Patients with Sneddon's syndrome had a progressive clinical course with increasing disability and cognitive deterioration; patients with PAS had a more benign course. Infarcts in territories of the main cerebral arteries were frequent in PAS, while leukoaraiosis and small lacunar infarcts were more common in Sneddon's syndrome. In 3 of 7 women initially diagnosed with PAS, the diagnosis was changed to systemic lupus erythematosus during follow-up. Differential diagnosis of Sneddon's syndrome and PAS is important, as early therapy is effective for the latter, more benign, condition.