Feasibility and oncological safety of post-adjuvant skin-sparing mastectomy (SSM) plus immediate breast reconstruction (IBR) cannot be evaluated by randomized trials. However, comparative study could modify guidelines for the oncosurgical treatment of invasive breast cancer. Our study compared the feasibility, oncological safety and esthetic outcome of SSM plus latissimus dorsi (LD) flap IBR after chemotherapy (CT) and radiotherapy (RT) with the standard management for invasive breast cancer: mastectomy as primary treatment, adjuvant CT and RT, and LD flap delayed breast reconstruction (DBR). Twenty-six selected patients with stages IIA-IIIA breast cancer were offered post-neoadjuvant SSM plus IBR with LD flap plus implant (IBR group). Seventy-eight other patients had primary mastectomy, adjuvant CT and RT, and LD-assisted DBR (DBR group). After 4.1 years (range 1-8) of follow-up, feasibility, oncological safety, and esthetic outcome were compared. Sixteen (61%) early complications were reported for the IBR group versus 44 (56%) for the DBR group (P = 0.645). Early implant loss was 0% in IBR versus 12% in DBR. IBR had 8 (30%) late complications versus 17 (21%) for DBR (P = 0.362). Capsular contracture and reconstruction failure rates were similar. Local recurrence was 7.7% (2/26) in IBR and 6.4% (5/78) in DBR (P = 0.823). Cosmetic evaluation by independent physicians and by the patients themselves was identical in the two groups. Our concept provides a basis for offering more women the opportunity to elect for immediate reconstruction, even in the setting of radiation therapy.