<p>Clozapine is the gold-standard treatment for treatment-resistant schizophrenia (TRS) but remains substantially underutilized in clinical practice. Advanced practice psychiatric nurses (APPNs) represent a growing segment of the psychiatric workforce, yet their knowledge, confidence, and prescribing practices related to clozapine have not been previously examined. A national cross-sectional survey was conducted among licensed psychiatric–mental health nurse practitioners and clinical nurse specialists practicing in the United States. The investigator-developed survey assessed demographics, clozapine-related knowledge, confidence, perceptions of risk, prescribing practices, and perceived barriers to clozapine use. Descriptive statistics summarized responses, and multiple linear regression examined predictors of confidence in clozapine management. A total of 155 APPNs completed the survey. Although most respondents reported prior clozapine-specific training and moderate to high levels of clozapine-related knowledge, the majority reported rarely or never prescribing clozapine. Fewer than one-quarter reported high confidence in initiating, titrating, or managing clozapine therapy. While most participants recognized clozapine as underutilized and perceived agranulocytosis as rare, only 20.5% reported being likely to prescribe clozapine following Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) elimination. Higher confidence was significantly associated with clozapine-specific training, prior initiation of clozapine, and more frequent prescribing, whereas knowledge level alone was not a significant predictor of confidence. Despite adequate knowledge, APPNs report limited confidence and clinical experience with clozapine, which may continue to impede its use following REMS elimination. Interventions emphasizing experiential learning, mentorship, and structured clinical support may be critical to improving clozapine access for individuals with TRS.</p>