Abstract To assess the possible involvement of humoral immunity in diffuse atherosclerosis, IgG, IgA, IgM, C3 and C4 were measured in the sera of 23 atherosclerotic subjects (at least 3 stenoses > 75% in the arteries of the limbs and neck, as assessed by panangiography) and of 20 controls (possible stenoses <40% documented by arteriography of the aortic arch and epi-aortic branches and “normal” response to exercise stress testing and Doppler ultrasonography of the arteries of the lower limbs). Age (59–69) and sex distribution did not differ significantly in the 2 groups. The following serum concentrations were higher in the atherosclerotic subjects than in the controls: C4 (28.7 ± 6.5 (1 SD) vs. 23.4 ± 3.8 mg/dl; P = 0.0013); IgA (323.3 ± 155,0 vs. 210.3 +- 87.9 mg/dl; P = 0.0020); and C3 (126.3 +- 16.9 vs. 111.0 ± 18.9 mg/dl; P = 0.0109). To assess whether these parameters were independently associated with atherosclerosis, a multiple logistic regression was performed, also including other variables which differed between the atherosclerotic group and the control group with P values less than 0.20 (cigarette smoking, arterial hypertension, body mass index, serum HDL-cholesterol, HDL-choiesteroi/total cholesterol ratio, serum triglycerides, IgG and IgM). In multivariate analysis only IgA ( P = 0.0012), C4 ( P = 0.0072), cigarette smoking ( P = 0.0141) and serum triglycerides ( P = 0.0177) were independently associated with atherosclerosis. Even taking into account the limitations arising from this retrospective study, the results suggest that serum IgA and C4 may be involved in many cases of diffuse atherosclerosis.