Adolescents and young adults (AYAs) with severe hemophilia use prophylaxis that requires a high level of adherence. The present study aimed to explore the underlying reason for adherence and non-adherence to prophylaxis in hemophilia from the perspective of AYAs. Patients and Methods: A qualitative study in Dutch AYAs with hemophilia (14-25 years) using prophylaxis was executed. Focus group interviews and individual interviews were recorded, transcribed, coded and analyzed using an iterative process. Member checking in three respondents was used to validate the potential model. Results: A total of 21 interviews were performed. Parental support decreased when AYAs gained more treatment responsibilities, which resulted in a higher risk for non-adherence. AYAs were weighing their potential bleeding risk per activity based on the wish to do what they prefer while also wanting to simultaneously feel safe. When bleeding with low impact on their daily life occurred, or when bleeding remained absent, AYAs felt safe and the perceived need for prophylaxis decreased. Conclusion: The level of treatment responsibility per AYA and estimated risks per activity were the two main underlying reasons for (non-)adherence. Clinical implications: We suggest using a conversation technique to discuss adherence, especially during bleeding assessment visits.