Inflammatory bowel disease (IBD) is a chronic and disabling disorder. Severity of IBD is prominent among refractory with patients with concomitant immune-mediated disorders. Among those patients, dual biological therapy (DBT) has been suggested as an alternative approach to spare steroids and avoid surgery. However, pieces of evidence on clinical outcomes among patients receiving DBT are still limited. We present two cases of IBD patients, with dermatological comorbidity, treated with a combination of vedolizumab and ustekinumab, identifying possible landmarks to address therapeutic choice. No patient experienced adverse events in the follow-up period and both obtained complete clinical remission. DBT may be an effective approach to consider in selected patients with refractory IBD with concomitant severe immune-mediated diseases taking into account medical history of the patient, presence, and type of concomitant extraintestinal manifestations, safety profile of selected DBT, licensed therapeutic indications, and costs.