Background: We aimed to investigate the association between acute carbon monoxide (CO) poisoning and the risk of internal malignancies, including hematologic malignancies. Methods: The study population was derived from the National Health Insurance Service (NHIS) database of Korea between 2002 and 2022. Adults diagnosed with CO poisoning and controls were included. Demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles of participants were retrieved from the NHIS database. Covariates potentially associated with disease outcomes were selected based on the available literature and biological plausibility, balanced between the two cohorts using inverse probability of treatment weighting, and applied to adjust multivariable models. Results: Overall, 42,874 patients with CO poisoning and 905,285 controls were included; both cohorts comprised 44.3% females. The mean age of the CO poisoning and controls was 51.5 and 50.9 years, respectively. Patients with CO poisoning had a 1.02-fold increase in the overall risk of malignancy (a 1.03-fold increase in solid organ malignancies and a 0.71-fold decrease in hematologic malignancies) compared with controls. The risk of internal malignancy was increased in the oral cavity (adjusted hazard ratio, 1.33; 95% confidence intervals, 1.19-1.49), lungs (1.39; 1.33-1.46), bone (1.68; 1.23-2.30), cervix (1.32; 95% CI, 1.17-1.49), and kidneys (1.14; 1.04-1.24). Conversely, the risk of internal malignancies was decreased in the thorax (0.59; 0.45-0.77), anus (0.14; 0.06-0.34), uterus (0.71; 0.60-0.82), ovaries (0.59; 0.45-0.77), prostate (0.89; 0.84-0.95), Hodgkin lymphoma (0.35; 0.20-0.61), non-Hodgkin lymphoma (0.67; 0.59-0.75), and multiple myeloma (0.36; 0.30-0.43). Conclusions: CO poisoning was associated with the development of internal malignancies.