Patients with human immunodeficiency virus (HIV) infection often require treatment with anticonvulsants either for treatment of seizures or occasionally for pain control. In this study, the authors determined if the anticonvulsants phenytoin, carbamazepine, and valproate could modulate HIV replication. These drugs activated HIV replication in latently infected monocytic cells but not in latently infected lymphocytic cells at clinically relevant dosages. The activation in the monocytic cells was as a result of transactivation of HIV long terminal repeat (LTR) and could be seen at therapeutic dosages whereas no effect was seen on LTR activation in lymphocytic cells. When the drugs were used in conjunction with known transactivators of HIV LTR such as Tat and phorbol-12-myristate-13-acetate (PMA), no additive or synergistic effect was noted. Although the clinical relevance of these observations needs to be determined, these observations may suggest that monitoring of cerebrospinal fluid (CSF) viral load maybe needed in HIV-infected patients treated with anticonvulsants, because HIV-infected macrophages are important in mediating HIV dementia.