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Kaposi sarcoma (KS) is the most common human immunodeficiency virus (HIV)-associated neoplasm (HIV-KS). Highly active antiretroviral therapy (HAART) results in a decrease in the incidence and prevalence of HIV-KS as well as in clinical improvement. However, in a subset of subjects who are HIV seropositive, KS may recrudesce early following the introduction of HAART as an immune reconstitution inflammatory syndrome (IRIS).The management of a patient who is HIV seropositive with rapid clinical worsening of oral KS lesions shortly after the initiation of HAART was documented. Repeated serologic testing for CD4+ T-cell count and microscopic examination of two biopsy specimens of the oral lesion, one taken before and the other taken after cytotoxic chemotherapy, followed by surgical excision was the treatment modality used.Microscopic examination of the incisional biopsy specimen taken from the oral lesion at the time of the initial consultation confirmed the clinical diagnosis of KS. The sequential serological tests showed a progressive increase in CD4+ T-cell counts that paralleled the rapid clinical worsening of the KS disease. This was consistent with the diagnosis of IRIS-associated HIV-KS. Subsequent cytotoxic chemotherapy brought about resolution of the IRIS and regression of the HIV-KS lesions. Microscopic examination of a biopsy specimen obtained after cytotoxic chemotherapy did not show any of the original KS. The residual palatal exophytic mass was excised.IRIS-associated HIV-KS is not a disease, but rather a temporary paradoxical immunoinflammatory reaction brought about by improvement in immune status following HAART. IRIS-associated HIV-KS can be controlled effectively by limited systemic cytotoxic chemotherapy in the setting of HAART. J Periodontol 2008;79:362–368.