The treatment options for patients with sarcoidosis are presently limited, and it is unclear which treatments are most effective for any given patient. We have identified a sarcoidosis phenotype characterized by CD4+ lymphopenia and resistance to conventional immunosuppressants, such as corticosteroids and methotrexate. Based on recent reports linking tumor necrosis factor (TNF)-α to regulatory T-cell (Treg) dysfunction, we hypothesized that sarcoidosis-associated CD4+ lymphopenia would resolve with anti-TNFα treatment. Five consecutive patients with CD4+ lymphopenia were treated with a chimeric anti-TNFα antibody (infliximab). Clinical disease manifestations and peripheral blood T-cell subsets were assessed before and after infliximab treatment. All patients experienced significant increases in absolute peripheral blood lymphocyte and CD4+ T-cell counts and demonstrated improvement in clinical disease manifestations in response to infliximab. No change in the distribution of T-cell subsets was noted. The presence of CD4+ lymphopenia identifies a distinct sarcoidosis phenotype that is particularly responsive to anti-TNFα therapy.