Several cases of patients with concomitant SLE and HIV infection have been reported in the literature; however, the effect of immunosuppressive therapy on HIV replication has not been described. We present the case of a 46 y/o woman with a ten-year history of HIV infection who was treated with IV cyclophosphamide for SLE nephritis. She had a positive HIV Western Blot just a few months before the diagnosis of SLE. Serum levels of HIV RNA had been persistently non-detectable since the assay became available. The patient was not receiving any antiretroviral therapy, raising doubts about the diagnosis of HIV infection. After 3 pulses of IV cyclophosphamide, HIV RNA levels went up to 135,720 copies/ml. Shortly after discontinuation of therapy viral levels were again undetectable. This case shows one of the possible clinical scenarios in patients with coexistent HIV infection and SLE. In our patient SLE appears to provide some immunologic defense against viral replication. Cross-reactivity of autoantibodies with HIV proteins may play a role in this mechanism. Effective immunosuppressive therapy suppresses this protection and leaves the immune system vulnerable to HIV reproduction. Treatment in these cases can be difficult and should be individualized in an attempt to achieve a balance between control of viral infection and SLE activity.