To test the effect of cyclosporine A (CsA) in mercuric chloride (HgCl2)-induced nephritis in the Brown-Norway (BN) rat, we treated groups of intoxicated rats with varying doses of CsA for a period of 2 months. All manifestations of HgCl2-induced disease were prevented in rats treated concurrently with CsA at either 7 or 10 mg/kg/day. Partial suppression was evident at lower daily doses, but not with bi-weekly CsA administration. The initial phase of HgCl2-induced nephritis could be completely suppressed with a short, 15 day course of CsA. The later phase of the disease could be tempered by CsA administration starting on day 10 after the first HgCl2 injection. The optimal regimen of 7 mg/kg/day for 60 days was not associated with any evidence of CsA toxicity. CsA appears to interfere with the polyclonal activation of B cells observed in HgCl2-induced autoimmune disease, accounting for its striking preventive and curative effect in this model.