Prophylaxis was recommended as the optimal treatment regimen for severe hemophilia by several expert committees. This led to increased utilization of prophylaxis and, subsequently, central venous access devices (CVADs). Although prophylaxis is the preferred treatment, episodic therapy is used by many. CVADs are employed to facilitate administration of prophylactic and episodic infusions; however, there are no data on the risk of CVAD-related infections for prophylaxis compared with episodic therapy. Data from the Study for the Prevention of Joint Disease in Preschool Children with Severe Hemophilia, a randomized clinical trial of prophylaxis versus episodic therapy, were used to evaluate the association between CVAD-related infection and treatment. The crude and adjusted rate ratios for first CVAD-related infection per 1000 CVAD days associated with episodic therapy versus prophylaxis were 1.42 (95% confidence interval: 0.46-4.40) and 1.23 (95% confidence interval: 0.33-4.56), respectively. Although we cannot make a definitive statement about treatment and CVAD-related infection risk, this study suggests that prophylaxis likely does not put children at higher risk of CVAD-related infection than episodic therapy. Given the need for CVADs in some children and the benefits of prophylaxis, we conclude there is no reason to recommend against prophylaxis on the basis of existing knowledge of CVAD-related infection risk.