Background: A significant proportion of patients with early-stage Her2-positive breast cancer are treated with neoadjuvant therapy (NAT). Previous studies suggested the presence of circulating tumor DNA (ctDNA(+)) after NAT was a significant predictor for recurrence in early-stage Her2-positive breast cancer. However, it is unknown whether the ctDNA(+) was able to guide adjuvant anti-Her2 regimen for patients with early-stage Her2-positive breast cancer?Methods: We enrolled 117 patients who had Her2-positive breast cancer and received NAT. CtDNA was collected before and after NAT as well as detected by Oncomine breast cell-free DNA assay. Adjuvant anti-Her2 regimens were classified as T-DM1 and non-T-DM1. Recurrence-free survival (RFS) was estimated by Kaplan-Meier method and hazard ratio (HR) with 95% confidence interval (CI) was analyzed by Cox proportional hazards regression model. Results: Of the 117 patients enrolled, there were 18 patients receiving adjuvant T-DM1 and 99 receiving trastuzumab (N = 70) or trastuzumab plus pertuzumab (N = 29). CtDNA(+) was observed in 79 patients before NAT while 32 patients remained ctDNA(+) after NAT. Multivariate Cox regression model showed that ctDNA(+) after NAT (HR 3.497 95% CI 1.364-8.964, p = 0.009) was an independently poor factor that predicted recurrence, after adjustment with clinical and pathologic parameters. Non-pCR was associated with an inferior trend of survival but not a statistically significant factor of recurrence. Patients who received adjuvant T-DM1 had a reduced risk of recurrence (HR 0.118, 95% CI 0.015-0.931, p = 0.043) in the multivariate analysis. Further analysis of the prognostic value of adjuvant T-DM1 therapy in context with and without ctDNA, we divided patients into 4 subgroups: ctDNA(-)/non-T-DM1, ctDNA(-)/T-DM1, ctDNA(+)/non-T-DM1 and ctDNA(+)/T-DM1. Our data revealed that patients with ctDNA(+)/T-DM1 had a significantly better RFS than those with ctDNA(+)/non-T-DM1 (p = 0.019). The 5-year RFS was similar between patients with ctDNA (+)/T-DM1 and those with ctDNA(-) after NAT. Conclusions: The presence of ctDNA in patients with early-stage Her2-positive breast cancer after NAT was independently associated with disease recurrence; however, ctDNA(+) after NAT became inconsiderable when patients were treated with adjuvant T-DM1 therapy, which represented ctDNA(+) as an important factor determining adjuvant anti-Her2 regimen.