Background Excess adiposity has been associated with an increased risk of several types of cancer. The relationship of fat tissue distribution in the body with these outcomes is less well known. Using data from the UK Biobank imaging substudy, we evaluated the prospective relationship between MRI-derived measurements of adipose tissue distribution and the risk of the major site-specific cancers associated with obesity. Methods Between 2014 and 2023, MRI measurements on adipose tissue distribution and volume were obtained from 49,044 (52.2% women) cancer-free UK Biobank participants. Quantitative MRI data included volumes of visceral and subcutaneous adipose tissues (VAT and ASAT), total abdominal fat/height squared (TAT/h2), and muscle fat infiltration (MFI). Cox proportional hazard models adjusted for cancer-specific risk factors were used to generate hazard ratios (HRs) and 95% confidence intervals (CI). Results Incident cancer cases of the breast (N+179), endometrium (n=30), colorectum (n=145), and kidney (n=50) were ascertained over a median follow-up of 4.5 years. In women, VAT, TAT/h2, and MFI were positively associated with risk of postmenopausal breast cancer, and ASAT was associated with increased risk of endometrial cancer. In men, VAT and TAT/h2 were positively associated with risk of colorectal cancer, while ASAT was associated with increased risk of kidney cancer. Conclusions The present study showed that increasing volumes of VAT, ASAT and MFI were associated with cancer at specific organ-sites, indicating a potential role for adipose tissue distribution in influencing cancer risk. Impact Both visceral and subcutaneous fat may have an impact on the risk of certain cancers.