How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control. Display omitted •Cancer patients with persistent COVID-19 infection have low humoral immune responses•Robust CD8+ T cell responses are unable to clear virus in B cell-depleted patients•Potent CD4+ T cell responses are in B cell-depleted patients with viral clearance Lyudovyk et al. analyze immunological factors required for SARS-CoV-2 clearance in patients with cancer. They observe delayed viral clearance in patients with impaired humoral immunity despite broad and functional antiviral CD8+ T cell responses. However, B cell-deficient patients with robust CD4+ T cell responses were frequently able to achieve efficient viral clearance.