Despite the increasing incidence of cervical artery dissection (CAD) due to chiropractic manipulation of the cervical spine, risk factors predisposing to vascular damage are still unknown. In the present study we measured fasting total plasma homocysteine (tHcy) concentration in 4 subjects with manipulation-related CAD selected from a larger series of patients with spontaneous dissection of the neck arteries (sCAD) and in a group of 36 control subjects. C677T MTHFR genotypes and 844ins68bp CBS genotypes were also determined. Median tHcy levels were significantly (P = 0.002) higher in patients with manipulation-related CAD (18.2 micromol/l, range 14.3 to 30.0) compared with controls (8.9 micromol/l, range 5 to 17.3) and not significantly different (P = 0.129) from those observed in patients with sCAD (13.9 micromol/l, range 7 to 32.8). No significant difference in the distribution of genotypes was observed in the three groups. Hyperhomocysteinemia may represent a potential risk factor for manipulation-related CAD, leading to structural abnormalities of the arterial wall and increasing the susceptibility to mechanical stress.