Antibody-mediated transient depletion of CD4þ cells enhances the expansion of tumor-reactive CD8þ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4þ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4þ cells promoted replacement of T-cell clones among CD4þ and CD8þ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4þ T-cell depletion and an increase in CD8þ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of antiCD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8þ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4þ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4þ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.