The purpose of the present study is to assess the gender-specific differences in the presentation and outcomes following Talar OsteoPeriostic grafting from the Iliac Crest (TOPIC) between male and female patients. A prospective comparative analysis was performed comparing consecutive female and male patients having been treated by the press-fit TOPIC procedure. Clinical comparative assessment preoperatively and at 12 months of follow-up included determination of the Numeric Rating Scale (NRS) scores for pain during walking (primary outcome), at rest and during stair-climbing. The Foot and Ankle Outcome Score (FAOS) was also assessed. A computed tomography (CT) scan was performed for lesion size, morphology and localization determination preoperatively as well as 10-12 weeks postoperatively to assess the union of the osteotomy site and at 1 year postoperatively to assess consolidation of the graft as well as intra-graft cyst development. A total of 48 patients (30 women, 18 men) were eligible for inclusion. Both men and women demonstrated significant functional improvements postoperatively concerning the clinical outcomes with no significant differences between men and women (n.s.) except for a significantly greater improvement in postoperative FAOS pain scores in women. Men presented with OLTs significantly larger in both surface area (208 mm for males versus 155 mm for females, p < 0.05) as well as lesion volume (3.0 cm for males versus 1.8 cm for females, p < 0.05). At 1-year postoperatively, all patients showed graft consolidation. Cyst formation was present in 11 females (37% of the group) and 10 males (59% of the group), respectively (n.s.). Both males and females showed clinically relevant improvements in the clinical outcomes after undergoing the TOPIC procedure with significant differences in preoperative lesion size. The TOPIC procedure is a good treatment strategy for large OLTs in both men and women. Level III, comparative prospective clinical cohort.