Valproic acid (VPA) reduces latent human immunodeficiency virus (HIV) reservoirs by activating resting CD4+ cells. This retrospective case-control study (n = 30) examined effects of VPA on markers of HIV progression. VPA was not associated with changes in cerebrospinal fluid viral loads (VL), plasma VL, or neuropsychological performance. VPA patients had a trend towards lower CD4+ cells (P = .08) at follow-up. Concurrent antiretrovirals did not alter these relationships. VPA does not induce viremia or promote disease progression and may be safe for clinical intervention.