Guideline developers consider cost-effectiveness evidence in decision making to determine value for money. This consideration in the guideline development process can be informed either by formal and dedicated economic evaluations or by systematic reviews of existing studies. To inform the American Society of Hematology guideline on the diagnosis of venous thromboembolism (VTE), we conducted a systematic review focused on the cost-effectiveness of diagnostic strategies for VTE within the guideline scope. We systematically searched Medline (Ovid), Embase (Ovid), National Health Service Economic Evaluation Database, and the Cost-effectiveness Analysis Registry, summarized, and critically appraised the economic evidence on diagnostic strategies for VTE. We identified 49 studies that met our inclusion criteria, with 26 on pulmonary embolism (PE) and 24 on deep vein thrombosis (DVT). For the diagnosis of PE, strategies including D-dimer to exclude PE were cost-effective compared to strategies without D-dimer testing. The cost-effectiveness of CT pulmonary angiogram (CTPA) in relation to ventilation-perfusion (V/Q) scan was inconclusive. CTPA or V/Q scan following ultrasound or D-dimer results could be cost-effective or even cost saving. For DVT, studies supporting strategies with D-dimer and/or ultrasound were cost-effective, supporting the recommendation that for patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. Our systematic review informed the ASH guideline recommendations about D-dimer, V/Q scan and CTPA for PE diagnosis and D-dimer and ultrasound for DVT diagnosis.