BACKGROUND: Early intervention in first-episode psychosis (FEP) is critical for long-term outcomes with antipsychotic medicines among the primary treatment options. However, existing clinical practice guidelines (CPGs) do not provide sex-specific recommendations, despite females experiencing distinct vulnerabilities to antipsychotic side-effects. In particular, hyperprolactinemia and cardiometabolic side-effects are associated with substantial subjective distress and potential long-term physical health risks for females across the reproductive lifespan. We aimed therefore to develop a CPG on the preferred antipsychotic medicines for females experiencing FEP. STUDY DESIGN: An international multidisciplinary panel, including experts-by-experience, used the GRADE-ADOLOPMENT process and AGREE II framework to adapt existing FEP guidelines for adults and adolescents. Key health questions were developed through stakeholder consultation and literature review. Critically important patient outcomes were prioritized, and evidence was synthesized on side-effect profiles, with recommendations agreed by consensus. The guideline algorithm was field-tested and externally reviewed by experts. STUDY RESULTS: Prolactin-elevation and cardiometabolic side-effects were prioritized in antipsychotic medicine selection for females. Medicines with higher risks-first-generation antipsychotics, olanzapine, quetiapine, risperidone, paliperidone, and amisulpride-are not recommended first-line. Aripiprazole is recommended as the preferred first-choice due to its consistently favorable prolactin and cardiometabolic profile. Alternative options with low or low-to-medium risk profiles are recommended for adults and adolescents, supported by shared decision-making tools. CONCLUSIONS: This is the first CPG addressing antipsychotic choice for females with FEP. By prioritizing critically important patient outcomes and lived experience, the guideline supports safer, sex-sensitive prescribing for females that may improve treatment acceptability, adherence, and equity in psychosis care.