Plasma and CSF concentrations of C4d and the circulating immune complex to C1q were measured in 27 patients with amyotrophic lateral sclerosis (ALS) or cervical spondylosis. There was no significant difference among groups in plasma C4d or in plasma or CSF concentrations of the circulating immune complex to C1q. The ALS group, however, had a significantly higher CSF concentration of C4d than the group with cervical spondylosis, as well as a higher C4d index (CSF to plasma C4d ratio x serum to CSF albumin ratio). These results suggest that augmented complement activation in the CNS occurs in ALS. Increased CSF concentration of C4d or raised C4d index may serve as a basis for differentiating ALS from cervical spondylosis.