To alleviate uncertainty in the specialized field of transgender medicine, mental and physical healthcare providers have introduced the rhetoric of evidence-based medicine (EBM) in clinical guidelines to help inform medical decision making. However there are no diagnostic tests to assess the effectiveness of transgender medical interventions and no scientific evidence to support the guidelines. Using in-depth interviews with a purposive sample of 23 healthcare providers, I found that providers invoked two strategies for negotiating the guidelines. Some used the rhetoric of EBM and closely followed clinical guidelines to contain uncertainty. Others flexibly interpreted the guidelines to embrace uncertainty. These findings raise questions about the effectiveness of EBM and guidelines in medical decision making. While trans medicine involves an identity and not a biomedical illness, providers use the same strategies to respond to uncertainty as they may in other medical arenas.