Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4⁺ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor V_α repertoires, suggesting antigenspecific expansion. CD4⁺ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-γ (IFN-γ)-secreting T helper type 1 (T_H1) cells, overwhelming static numbers of T_H2 (CD4⁺GATA-binding protein-3 (GATA-3)⁺) and regulatory forkhead box P3 (Foxp3)⁺ T cells. CD4⁺ (but not CD8⁺) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through T_H2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab′)₂ fragment, reduces the predominance of T_H1 cells over Foxp3⁺ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4⁺ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.