Background: Metaanalyses have demonstrated that 5% of initially HER2 negative breast cancer patients switch to HER2 positive during the course of the disease. Whether there is a difference in benefit from standard HER2 targeted therapies between patients initially HER2 positive and patients switching from negative to positive is unclear. We used data from the PRAEGNANT registry to compare the outcome of those patients. Methods: PRAEGNANT is a prospective advanced breast cancer registry (NCT02338167) focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis compared progression-free survival (PFS) with standard HER2 targeted therapies between patients with tumors initially HER2 negative and switched to HER2 positive and patients with tumors that were initially HER2 positive adjusted for age and hormone receptor status. Results: At the time of this analysis 4061 patients with MBC were included in the PRAEGNANT registry, 49 of which met the requirements for this analysis. Median age was 56 (IQR 48-64) years and 87.8% of the patients were hormone receptor positive. At first diagnosis 15 patients were HER2 negative and 34 patients were HER2 positive. Within a median observation time of 9 months (95%CI: 3.8, 23.7) 35 PFS events occurred. Median observation time was 9 months (95% CI: 3.8, 23.7). Initially HER2 positive patients had a longer progression-free survival (HR = 0.49, 95% CI (0.24, 1.03), p = 0.07) as compared to initially HER2 negative patients switched to HER2 positive. The 1- and 2-year-PFS rates were also higher for patients initially HER2 positive: 1-year-PFS: 52% (95% CI: 36%, 73%) versus 26 % (95% CI: 12%, 52%); 2-year-PFS: 44% (95% CI: 29%, 67%) versus 19% (95% CI: 7%, 50%). Conclusions: Median PFS and 1- and 2-year PFS rate seem to be better in patients HER2 positive at initial diagnosis receiving standard HER2 directed therapies. Although our result has to be interpreted with caution because of the small cohort and the retrospective nature of our analysis, it justifies prospective research including the group of initially HER2 negative patients switched to HER2 positive as a distinct entity. Clinical trial information: NCT02338167.