This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR = 0.82, 95% CI: 0.73-0.93; Z = 3.00; P = 0.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR = 1.33, 95% CI: 1.18-1.50; Z = 4.70; P < 0.00001), diarrhea (RR = 14.59, 95% CI: 7.69-27.67; Z = 8.20; P < 0.00001), and dermatologic toxicity (RR = 3.10, 95% CI: 1.61-5.96; Z = 3.39; P = 0.007), but none was found for neutropenia (RR = 1.38, 95% CI: 0.82-2.31; Z = 1.22; P = 0.22) or CHF (RR = 0.14, 95% CI: 0.02-1.17; Z = 1.02; P = 0.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2-positive breast cancer patients with no additional cardiac events. Trastuzumab, which is still the first-line therapy in breast cancer, increases the pCR rate more than lapatinib.