Patients in this analysis, as previously described, were frequently immunocompromised or had serious comorbid conditions and most commonly presented with pulmonary disease. The overall case-fatality rate for this cohort was high. We found that while a substantial minority of patients did not receive IDSA guideline-recommended initial therapy, the receipt of alternative initial treatments was not equally distributed across all C. gattii infections. Fewer patients with pulmonary WY 14643 infections compared with central nervous system infections received IDSA guideline-recommended initial therapy. Among patients with isolated pulmonary infections, fewer with severe pulmonary infections received recommended initial therapy compared with those persons with non-severe infections. Among the patients who received alternate initial treatment, most were ‘under-treated’, failure to receive any treatment. Receipt of an alternative initial therapy was associated with a non-significant trend towards increased mortality in the three months after diagnosis, particularly among patients with pulmonary infections. There are a number of reasons why IDSA-recommended initial therapy might not have been used with patients in this cohort. While infectious disease clinicians are likely to be aware of the IDSA guidelines for cryptococcal disease, many patients are initially treated by clinicians without formal infectious disease training who may not be aware of the IDSA guidelines. Specifically, they may not be aware that severe pulmonary cryptococcosis should be treated in the same way as central nervous system cryptococcosis, leading to under-treatment of patients with severe pulmonary infections. Additionally, as C. gattii infections in the United States Pacific Northwest appear to be clinically different from C. gattii infections in other areas of the world, some clinicians who are aware of the IDSA guidelines in Oregon and Washington State may initially deviate from IDSArecommended therapy due to concerns about the generalizability of the guidelines to their patients with C. gattii infection. Finally, clinicians may not have used guideline-recommended initial therapy due to matters beyond their control, such as patient contraindications to medications, insurance restrictions, or drug shortages. While we were unable to evaluate why clinicians chose, in a minority of patients, to pursue alternative treatments, our data suggests that there might be some benefit in adhering to IDSA guideline-recommended initial treatment in United States Pacific Northwest C. gattii patients, particularly those with pulmonary disease. Further research into the reasons for use of alternative initial treatment regimens is needed. Pulmonary cryptococcosis presents a number of clinical challenges in diagnosis and treatment.