Impairment of CD4⁺ T lymphocyte responses to human immunodeficiency virus (HIV)‐derived antigens is the classic immunological defect observed during the chronic phase of HIV‐1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV‐specific CD4⁺ T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV‐specific CD4⁺ T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that therapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV‐1 infection preserves patterns of functional reactivity within the HIV‐specific CD4⁺ T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV‐1 infection to effect substantial immune preservation.