Venous thromboembolism can be precipitated by both genetic and acquired factors, but the role of testosterone therapy is less clear. Here, we present a 17-year-old transgender adolescent, transitioning from female to male, receiving both estrogen and testosterone therapy, who developed a pulmonary embolism without an underlying genetic thrombophilic condition. As transgender medical care evolves, the use of testosterone as cross-sex hormone therapy in adolescents is likely to increase. Our review suggests that care must be taken when initiating treatment with testosterone, and modification of other thrombophilic risks should be explored before starting therapy in this population.