Atrial fibrillation (AF) and cancer are often co-morbid, thought due to increased risk of AF from cancer and cancer-related treatments. However, associations between AF and cancer may also be due in part to shared risk factors and/or detection bias from more frequent healthcare contacts. To determine the risk of cancer incidence and cancer-related mortality in patients with newly diagnosed AF compared to patients without AF. We prospectively examined the association between new-onset AF and subsequent diagnosis of incident cancer in 24,978 patients without history of cardiovascular disease, AF, or cancer enrolled in the VITAL Rhythm Study. Patients were evaluated for new diagnoses of AF and for subsequent cancer diagnoses by review of the medical record. Multivariable Cox proportional hazards regression models were constructed to compare cancer incidence as well as the risk of cancer-related mortality between patients with and without new diagnoses of AF. In the median follow-up period of 6.3 years, 4.0% of the study cohort (n=1003) developed new-onset AF and 6.7% (n=1661) were diagnosed with cancer. After adjustment for age, the risk of incident cancer was higher in the AF patients compared to those without an AF diagnosis (HR 1.68, 95% CI 1.28-2.21, p<0.001). This remained significant in multivariable models controlling for age, BMI, smoking, alcohol use, and other shared cancer and AF risk factors (HR 1.51, 95% CI 1.14-2.01, p=0.004). The relative risk of cancer-related mortality was also higher among the participants with incident AF (HR 2.28, 95% CI 1.46-3.57, p<0.001). This relationship remained significant and was not materially altered after controlling for shared risk factors (HR 2.33, 95% CI (1.46, 3.71) p<0.001). After stratifying by sex, there were no significant differences in the association of AF with cancer incidence or cancer-related mortality. Patients with new diagnoses of AF are more likely than those without AF to be diagnosed with cancer and to experience cancer-related mortality even after controlling for shared risk factors. Although higher rates of cancer diagnoses may stem from more frequent healthcare contact, the increased risk of cancer-related mortality in patients with AF argues against detection bias entirely accounting for the association between AF and cancer.