Abstract Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Previously, a study of patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor (ORAL Surveillance) found increased rates of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events (MACE), and venous thromboembolism with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to inform clinical decision-making via data review. Methods We reviewed ORAL Surveillance and tofacitinib UC clinical program data. Results In risk-enriched patients with RA in ORAL Surveillance, three differential risk factors were identified: age ≥65 years; current/past long-time smoking; atherosclerotic cardiovascular disease (ASCVD) history (MACE only). In patients with RA without differential risk factors, no risk differences in these safety outcomes with tofacitinib versus TNFi were detected. There are insufficient data on the risk with tofacitinib of safety outcomes in patients with UC with differential risk factors, but results highlighted that absolute risk of these safety outcomes with tofacitinib was low in patients with UC without differential risk factors, and similar to that for tofacitinib and TNFi in ORAL Surveillance patients without differential risk factors. Conclusions In the absence of prospective UC safety studies of sufficient size/duration, ORAL Surveillance results should be considered for UC as a precautionary approach. The differential risk factors for safety outcomes with tofacitinib versus TNFi (age ≥65 years and current/past long-time smoking or ASCVD history [MACE)]) provide a framework for an individualized risk factor-based approach to clinical decision-making on treatment with tofacitinib.