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Purpose: This study is to evaluate the effectiveness of a PPOS protocol in poor prognosis patients undergoing IVF with DuoStim and PGT-A versus the conventional protocol with GnRH antagonist. Methods: Retrospective cohort study encompassing 444 couples obtained matching one PPOS-DuoStim with two antagonist-DuoStim cycles at a private IVF center between 2020 and 2023 (average maternal age: 40 years, average cumulus–oocyte complexes collected after the first stimulation: 5). The study was powered to exclude a two-sided different euploid blastocyst rate per MII oocytes (EBR per MII) in the two groups (alpha = 0.05, power = 0.9, effect size = 0.3). All cycles involved ICSI, blastocyst stage PGT-A, and single vitrified-warmed euploid transfers. We compared all embryological and clinical outcomes within each group (first vs. second stimulations), and among the two study arms (first stimulation vs. first stimulation; second stimulations vs. second stimulation; overall). The overall EBR per MII was the primary study outcome. The cumulative-live-birth-rate per concluded cycles (CLBR) was the main secondary outcome. Results: In the second stimulations, we obtained a greater number of COCs and MIIs in both antagonist- and PPOS-DuoStim groups. No difference was observed for all embryological and clinical outcomes when comparing the two stimulations within each group. All embryological and clinical outcomes were comparable also between the two groups, including the EBR per MII. To date, 285 and 121 antagonist- and PPOS-DuoStim cycles were concluded. The CLBR was comparable between the groups: 26% vs. 29%. Conclusions: PPOS-DuoStim holds potential for being an efficient, patient-friendly, and possibly cost-effective approach that does not compromise treatment efficacy. Future investigations must explore PPOS effect on follicular recruitment, neonatal, and long-term outcomes. [ABSTRACT FROM AUTHOR]