This study aims to assess safety and effectiveness of pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant treatment (NeoT) of HER2-positive breast cancer. Two consecutive retrospective cohorts ( = 94, 2012-2015 and 2015-2017) of adult women with HER2-positive breast cancer, receiving NeoT at the breast clinic in Portugal (IPO-Porto), were followed. All patients had surgery and received trastuzumab as adjuvant therapy. The 2012-2015 cohort received doxorubicin, cyclophosphamide, docetaxel plus trastuzumab, whereas the 2015-2017 cohort was treated with the same protocol plus pertuzumab. The 2012-2015 cohort was older (median 53 years), with locally advanced tumors (48.1%), mostly hormone receptor positive (59.3%). The 2015-2017 cohort was younger (median 43 years) with 60% operable tumors. Pathologic complete response (pCR) improved in the second cohort, while maintaining a good safety profile and tolerability. Clinical staging ( = 0.001) and hormone receptor ( = 0.003) were significant predictors of pCR, but not treatment regimen ( = 0.304). Further research with larger samples and longer follow-up is needed to understand the clinical differences. Clinical effectiveness of treatment should also be measured through overall and progression-free survival.