Background <p>Electrographic flow (EGF) mapping allows for the near real-time visualization of atrial wavefront propagation. Two factors have been found to be associated with higher rates of atrial fibrillation (AF) recurrence: presence of active extra-pulmonary vein (PV) sources and low electrographic flow consistency (EGFC) representing chaotic flow and abnormal atrial substrate. Based on these characteristics, EGF phenotypes have been identified: Type I patients have no sources + high EGFC, Type II have sources + high EGFC, Type III have sources + low EGFC, and Type IV have no sources + low EGFC.</p> Objective <p>Determine the sex differences in EGF phenotypes and post-ablation outcomes.</p> Methods <p>Patients were pooled from three prospective clinical trials: <i>FLOW-AF</i>, <i>EVAL-AF</i>, and the <i>AF-FLOW Global Registry</i>. From these trials, 104 persistent AF (PeAF) or long-standing PeAF patients underwent EGF mapping in 5 standardized, biatrial basket positions. Phenotyping into one of the 4 types was performed from post-PVI maps, and patients were followed for up to 12&#xa0;months post-procedure, which included PVI-only and PVI + EGF-guided source ablation procedures. Outcomes were compared by chi-square tests, <i>z</i>-tests of proportions, logistic regression, and cox proportional models.</p> Results <p>There were 30 (29%) female patients with mean age 70 ± 8&#xa0;years and 74 (71%) males with mean age 64 ± 10&#xa0;years. There was no significant difference in left atrial dimension, left ventricular ejection fraction, or number of prior ablations between men and women. Men and women had distinct phenotype distributions (<i>p</i> = 0.007). Women had more sources and higher EGFC so were more likely than men to present as Type II (43% vs. 20%, <i>p</i> = 0.016), including when controlling for confounders (aOR 3.17, <i>p</i> = 0.024). Outcomes of these Type II patients were most improved by PVI + EGF-guided ablation when compared to PVI-only (91% vs. 50%, <i>p</i> = 0.038) without differences in intra-phenotype responsiveness to treatment by sex or intragroup hazard ratios by sex. Trends in phenotype differences of women vs. men were also present among those with other factors that increased CHA₂DS₂-VASc scores generally.</p> Conclusions <p>Female patients with PeAF are more likely to have extra-PV sources but healthy underlying substrate (Type II), which responds favorably to PVI + targeted source ablation. Ablation strategies should consequently target an individual’s mechanism of disease.</p> Trial registration numbers <p><i>FLOW-AF</i>: NCT04473963, <i>FLOW EVAL-AF</i>: NCT06260670, <i>AF-FLOW</i> Global Registry: NCT05481359.</p> Graphical abstract <p></p>