T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8⁺ T cells by class I MHC. However, CD4⁺ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8⁺ or CD4⁺ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non–small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4⁺ T cells that recognized the recurrent KRAS^G12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. Two different T-cell receptors (TCR) specific for KRAS^G12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD–specific TCR in the tumor but not nonadjacent lung. Our results showed that CD4⁺ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4⁺ neoantigen-specific T cells and elucidate their role in human antitumor immunity.