Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinfl ammatory senescence-associated secretory phe- notype. Many genotoxic chemotherapies target proliferating cells nonspecifi cally, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic infl ammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our fi ndings in mice, the risk of chemotherapy-induced fatigue was signifi cantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These fi ndings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.