Background: Before integrating prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) into routine care, it is important to assess if the benefits justify the differences in resource use. Objective: To determine the cost-effectiveness of PSMA-PET/CT when compared with conventional imaging. Design, setting, and participants: A cost-effectiveness analysis was developed using data from the proPSMA study. proPSMA included patients with high-risk prostate cancer assigned to conventional imaging or 68Ga-PSMA-11 PET/CT with planned health economics data collected. The cost-effectiveness analysis was conducted from an Australian societal perspective. Intervention: 68Ga-PSMA-11 PET/CT compared with conventional imaging (CT and bone scan). Outcome measurements and statistical analysis: The primary outcome from proPSMA was diagnostic accuracy (nodal and distant metastases). This informed a decision tree analysis of the cost per accurate diagnosis. Results and limitations: The estimated cost per scan for PSMA PET/CT was AUD$1203, which was less than the conventional imaging cost at AUD$1412. PSMA PET/CT was thus dominant, having both better accuracy and a lower cost. This resulted in a cost of AUD$959 saved per additional accurate detection of nodal disease, and AUD$1412 saved for additional accurate detection of distant metastases. The results were most sensitive to variations in the number of men scanned for each 68Ga-PSMA-11 production run. Subsequent research is required to assess the long-term costs and benefits of PSMA PET/CT-directed care. Conclusions: PSMA PET/CT has lower direct comparative costs and greater accuracy compared to conventional imaging for initial staging of men with high-risk prostate cancer. This provides a compelling case for adopting PSMA PET/CT into clinical practice. Patient summary: The proPSMA study demonstrated that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) better detects disease that has spread beyond the prostate compared with conventional imaging. Our analysis shows that PSMA PET/CT is also less costly than conventional imaging for the detection of disease spread. This research was presented at the European Association of Nuclear Medicine Scientific Meeting in October 2020. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) was more effective and less costly compared with conventional imaging in the short term. Over a lifetime horizon, better diagnostic accuracy resulted in more men receiving appropriate treatment, which translated into PSMA PET/CT being cost-effective on the basis of estimated survival and quality-of-life gains.