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Whereas CD4+ T cells conventionally mediate antitumor immunity by providing help to CD8+ T cells, recent clinical studies have implied an important role for cytotoxic CD4+ T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4+ T cell responses and their regulation by major histocompatibility complex class II (MHC II) in the skin. Intravital imaging revealed prominent interactions of CD4+ T cells with tumor debris-laden MHC II+ host antigen-presenting cells that accumulated around tumor cell nests, although direct recognition of MHC II+ melanoma cells alone could also promote CD4+ T cell control. CD4+ T cells stably suppressed or eradicated tumors even in the absence of other lymphocytes by using tumor necrosis factor–α and Fas ligand (FasL) but not perforin-mediated cytotoxicity. Interferon-γ was critical for protection, acting both directly on melanoma cells and via induction of nitric oxide synthase in myeloid cells. Our results illustrate multifaceted and context-specific aspects of MHC II–dependent CD4+ T cell immunity against cutaneous melanoma, emphasizing modulation of this axis as a potential avenue for immunotherapies. Editor's summary: CD4+ T cells have been primarily appreciated for their helper functions in antitumor immune responses, but the extent to which they directly contribute to tumor killing remains unclear. Using a mouse model of cutaneous melanoma, Bawden et al. characterized the effector functions of CD4+ T cells in generating protective antitumor immunity. Melanoma-specific CD4+ T cells infiltrated tumors, adopted diverse effector states, and could provide tumor protection independent of other lymphocytes. Whereas MHC II expression by melanoma cells was sufficient to activate protective CD4+ T cell–mediated immunity, host antigen-presenting cells could also drive protection. CD4+ T cells provided protection through multiple partially redundant cytotoxicity pathways, including TNF and Fas ligand, but also by activating IFN-γ–dependent nitric oxide production in myeloid cells. Together, these results demonstrate that tumor-infiltrating CD4+ T cells are equipped to contribute to tumor control through multiple helper and effector modes. —Claire Olingy [ABSTRACT FROM AUTHOR]