Background: Spontaneous cervical artery dissection (sCAD) is a nonatherosclerotic vascular disease of unknown etiology. Mild elevation of total plasma homocysteine (tHcy) levels may be a risk factor for sCAD, but the precise mechanism remains unknown. On the other hand, mild hyperhomocysteinemia is also associated with ischemic stroke related to atherothrombotic or small artery disease. We undertook a case-control study to compare the prevalence of mild hyperhomocysteinemia and tHcy levels between patients with a first ischemic stroke due to sCAD and healthy volunteers, as well as patients with a first ischemic stroke due to atherothrombotic or small artery disease. Methods: Fasting tHcy levels were determined in 346 consecutive patients with a first ischemic stroke due to sCAD (n = 86) and atherothrombotic or small artery disease (n = 260) within 24 h after the onset of symptoms, and in 100 healthy volunteers. Results: Mild hyperhomocysteinemia was more prevalent in patients with sCAD causing ischemic stroke (n = 33, 38%) than in healthy volunteers (n = 23, 23%; p = 0.034), and less prevalent than in patients with ischemic stroke due to atherothrombotic or small artery disease (n = 149, 57%; p = 0.001). Mean fasting tHcy levels of patients with ischemic stroke caused by sCAD showed a trend to be higher (11.4 +/- 3.8 mumol/l) than those of healthy volunteers (10.2 +/- 3.0 mumol/l, p = 0.61), but were lower than those of patients with stroke due to atherothrombotic or small artery disease (13.6 +/- 6.6 mumol/l, p = 0.002). Conclusion: Our results suggest that mild hyperhomocysteinemia may be a risk factor for sCAD causing ischemic stroke, but further studies are needed to identify a possible mechanism. This study confirms the association of hyperhomocysteinemia with ischemic stroke due to atherothrombotic or small artery disease.