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Background: In mice models of cancer and human tissues samples, disturbance of the gut microbiota can reduce the effectiveness of chemotherapy and immunotherapy. There is limited evidence in humans whether antibiotics impact on the effectiveness of cancer treatments. We evaluated the associations between antibiotic use before cancer diagnoses and long-term mortality. Methods: Primary care data from general practices contributing to the English Clinical Practice Research Datalink (CPRD) and Welsh Secure Anonymised Information Linkage (SAIL) linked to Cancer Registries (CR) and Office for National Statistics (ONS) mortality records were used. Two cohort studies involving cancer patients (15 types) exposed to antibiotics before cancer diagnosis were identified. Recent, previous and past antibiotic users were compared using Cox regression models. Findings: 129 990 cancer patients from the National Cancer Registration and Analysis Service (NCRAS) linked to CPRD and 131 330 from the Welsh Cancer Intelligence Surveillance Unit (WCISU) were included. In comparison with past antibiotic users, patients who used antibiotics in the recent past before their cancer diagnosis and were mainly treated with chemotherapy or immunotherapy presented increased hazards ratio (HR) for mortality consistently in both cohorts; for leukaemia, the HR in NCRAS was 1·40 (95% CI 1·22-1·60), for lymphoma 1·19 (95% CI 1·06-1·33), for melanoma 1·31 (95% CI 1·12-1·54), and for myeloma 1·19 (95% CI 1·04-1·36). HR for cancer of the uterus, breast, urinary, colorectal, and kidney cancer followed the same trend in both CRs. Sensitivity analyses based on general practice records suggested comparable results to those from CRs. Interpretation: This study supports the hypothesis that prior use of antibiotics may reduce the effectiveness of chemotherapy and immunotherapy, potentially through disruption to the gut microbiota. Although not providing definitive results, the biological plausibility of the findings does support the need for judicious use of antibiotics. Funding: Department of Health and NIHR. Declaration of Interest: We declare no competing interests. Ethical Approval: The protocol was approved by the Independent Scientific Advisory Committee for CPRD research (protocol number 18_198) and SAIL’s Information Governance Protocol Review Panel (protocol number 0855).