Lipofilling has recently gained popularity as a tool in primary treatment of breast cancer, and its association with two-stage implant breast reconstruction is considered as standard treatment in many centers. However, no data are available about the longterm results of the association of lipofilling in combination with expander-implant reconstruction. A retrospective analysis was conducted on patients treated between January 2010 and December 2014. Two groups were compared. Group 1 had a standard expander-implant two-stage reconstruction. Group 2 underwent hybrid breast reconstruction (HBR). Patient characteristics, hospitalization, outcomes, reoperation details, outpatient visits, and evaluation questionnaires were taken into consideration. Intergroup comparison was performed using Wilcoxon Mann-Whitney U test and Pearson's chi-square test or Fisher's exact test for categorical variables. Two hundred fourteen patients were evaluated: 130 patients in group 1 and 84 patients in group 2. Group 2 showed significant benefits over group 1 in terms of capsular contracture rate, breast pain, and displacement/rotation of the implant (p = 0.005). The HBR protocol is associated with lower rate of capsular contracture, less breast pain at long follow-up times, and lower overall rates of revision surgery compared to standard expander-implant reconstruction. A specific cost analysis will help further clarify the advantages of this protocol over a standard procedure. Level of Evidence: Level III, risk/prognostic, therapeutic study.