The factors responsible for the phenotypic heterogeneity of memory CD4 T cells are unclear. In the present study, we have identified a third population of memory CD4 T cells characterized as CD45RA⁺CCR7^– that, based on its replication history and the homeostatic proliferative capacity, was at an advanced stage of differentiation. Three different phenotypic patterns of memory CD4 T cell responses were delineated under different conditions of antigen (Ag) persistence and load using CD45RA and CCR7 as markers of memory T cells. Mono‐phenotypic CD45RA^–CCR7⁺ or CD45RA^–CCR7^– CD4 T cell responses were associated with conditions of Ag clearance (tetanus toxoid‐specific CD4 T cell response) or Ag persistence and high load (chronic HIV‐1 and primary CMV infections), respectively. Multi‐phenotypic CD45RA^–CCR7⁺, CD45RA^–CCR7^– and CD45RA⁺CCR7^– CD4 T cell responses were associated with protracted Ag exposure and low load (chronic CMV, EBV and HSV infections and HIV‐1 infection in long‐term nonprogressors). The mono‐phenotypic CD45RA^–CCR7⁺ response was typical of central memory (T_CM) IL‐2‐secreting CD4 T cells, the mono‐phenotypic CD45RA^–CCR7^– response of effector memory (T_EM) IFN‐γ‐secreting CD4 T cells and the multi‐phenotypic response of both IL‐2‐ and IFN‐γ‐secreting cells. The present results indicate that the heterogeneity of different Ag‐specific CD4 T cell responses is regulated by Ag exposure and Ag load.