The present study examined in the spontaneously diabetic BB/OK rat whether a relationship exists between the appearance of complement‐dependent antibody‐mediated cytotoxicity (C'AMC) in serum and the relative β cell volume density determined in pancreatic biopsies. C'AMC was estimated by 51Cr release from prelabeled major histocompatibility complex‐compatible neonatal rat islet cells afterexposure to rat serum and rabbit complement. Fifty‐one percent (72/141) of sera from BB/OK rats with newly diagnosed diabetes were positive for C'AMC. At onset of hyperglycemia, insulin‐immunoreactive β cells were only detectable in pancreas biopsies of 25% (10/40) of the BB/OK rats who displayed mild hyperglycemia(plasma glucose 8.3—13.0 mmol/l) and low serum C'AMC. A twofold increase (p < 0.01) of C'AMC and loss of the remaining β cells was evident in untreated animals upon their reexamination within 1 week after diagnosis of hyperglycemia. Initiation of insulin therapy prevented neither the increase in C'AMC activity nor the decrease in the β cell volume density. In contrast, three out of four mildly hyperglycemic BB/OK rats treated with cyclosporin A maintained both their initial C'AMC levels and relative β cell volume density not only throughout the treatment period (4 weeks) but also for at least 4 weeks thereafter. In one additional animal receiving cyclosporin A no protection of the remaining β cells could be achieved and C'AMC levels were markedly increased. It is concluded that the appearance of increased C'AMC in serum may reflect autoimmune reactions against the islet β cells of spontaneously diabetic BB/OK rats. Theincrease of C'AMC seen in untreated as well as insulin‐treated BB/OK rats, whichwere even devoid of β cells, suggests that C'AMC activity appears secondary to the loss of β cells. These results do not support the hypothesis of a direct β cell destruction via intrainsular complement activation. Copyright © 1990 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim