Animal studies indicate that the immune system is one of the most sensitive targets of the toxic effects of 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD). TCDD inhibits immunoglobulin secretion and decreases resistance to bacterial, viral, and parasitic infections in exposed animals. Nearly 20 years after the Seveso, Italy, accident, we measured immunoglobulin and complement plasma levels in a random sample of the population in the most highly exposed zones (n = 62) and in the surrounding noncontaminated area (n = 58). Plasma IgG levels decreased with increasing TCDD plasma concentration (r = -0.35, p = 0.0002). Median IgG concentration decreased from 1,526 mg/dL in the group with the lowest (< 3.5 ppt) TCDD levels to 1,163 mg/dL in the group with the highest (20.1-89.9 ppt) TCDD levels (p = 0.002). The association was significant (p = 0.0004) after adjusting for age, sex, smoking, and consumption of domestic livestock and poultry in multiple regression analysis and persisted after exclusion of subjects with inflammatory diseases and those using antibiotics or nonsteroidal anti-inflammatory drugs. IgM, IgA, C3, and C4 plasma concentrations did not exhibit any consistent association with TCDD levels. We performed a systematic review of all the articles published between 1966 and 2001 on human subjects exposed to TCDD reporting information on circulating levels of immunoglobulins and/or complement components. The literature indicates that the evidence for effects of TCDD on humoral immunity is sparse. Methodologic issues, results, and possible sources of variation between studies are discussed. The possible long-term immunologic effects of TCDD exhibited by the participants of the present study, coupled with the increased incidence of lymphatic tumors in the area of the accident, warrant further investigation.