For some years now, direct-acting oral anticoagulants (DOACs) have entered the clinical practice for stroke prevention in non-valvular atrial fibrillation (NVAF) or prevention and treatment of venous thromboembolism (VTE). However, there is uncertainty on DOAC use in some clinical scenarios not fully explored by clinical trials, but commonly encountered in the real world. We report a Delphi Consensus on DOAC use in NVAF and VTE patients. The consensus dealt with 16 main topics: (1) clinical superiority of DOACs compared to VKAs; (2) DOACs as a first-line treatment in patients with AF; (3) therapeutic options for patients undergoing electrical cardioversion; (4) selection of patients suitable for switching from VKAs to DOACs; (5) and (7) role of general practitioners in the follow-up of patients receiving a DOAC; (6) duties of Italian oral anticoagulation therapy centers; (8) role of therapy with DOACs in oncological patients with NVAF; (9) role of DOACs in oncological patients with VTE; (10) methods for administration and therapy compliance for DOACs; (11) drug interactions; (12) safety of low doses of DOACs; (13) therapeutic management of frail patients with NVAF; (14) therapeutic management of NVAF patients with glomerular filtration rate <30 ml/min (15); advantages of DOACs for the treatment of frail patients; (16) limitations on therapeutic use of DOACs. Sixty-two cardiologists from Italy expressed their level of agreement on each statement by using a 5-point Likert scale (1: strongly disagree, 2: disagree, 3: somewhat agree, 4: agree, 5: strongly agree). Namely, votes 1-2 were considered as disagreement while votes 3-5 as agreement. Agreement among the respondents of ≥66% for each statement was considered consensus. A brief discussion about the results for each topic is also reported.