Background: HER2 belongs to the same family with EGFR and is known as an important cancer driver gene. Kinase domain insertions and deletions (KD indels) are frequent driver mutations in both EGFR and HER2. The most common HER2 KD indels are the exon 20 insertions while others are rarely reported. Our study aimed to investigate the role of less common HER2 KD indels in solid tumors. Methods: This study was performed in 63,267 Chinese patients including 53,591 patients with lung cancer, 5,888 patients with colorectal cancer, 3,774 patients with breast cancer and 14 patients with renal pelvis cancer. Tissue or plasma samples from the patients were subjected to capture-based targeted sequencing covering HER2 and other cancer related genes. The sequencing data of each patient were retrospectively collected and analyzed. The HER2 exon 18/19 indels identified in our study were compared with data from COSMIC and MSKCC. In vitro analysis in Ba/F3 cell lines was performed to assess drug response of different HER2 exon 18/19 indels. Results: We identified recurrent HER2 KD indels in exon 18 and 19, with a frequency of 0.04% (25/63,267). The data from COSMIC and MSKCC reported the prevalence of HER2 exon 18/19 indels ranging from 0.04% to 0.23% among breast, cervical, and pancreatic cancers. In our study, HER2 exon 18/19 indels were identified in 20 patients with lung cancer (0.037%), two with colorectal cancer (0.034%), two with breast cancer (0.053%) and one with renal pelvis cancer (7.143%). Only two patients (8%) harbored concurrent actionable driver mutations including EGFR mutation and MET amplification. Meanwhile, high level of normalized allelic frequency of HER2 exon 18/19 indels was presented in most patients (22/25, 88%). In lung cancer, the presence of EGFR driver mutation was less common in patients with HER2 exon 18/19 indels than wild type HER2 (5% vs. 47.4%, p < 0.01). The rates of concurrent driver mutations in lung cancer were comparable between HER2 exon 18/19 indels and the two established HER2 drivers, exon 20 insertions and S310 mutations. The in vitro proliferation assay demonstrated that E698_P699insLL mutation in HER2 exon 18 and L755_E757delinsPQ mutation in HER2 exon 19 both conferred a survival advantage to Ba/F3 cells. Dose-response curves showed inhibitory effects on cell viability of several HER2 tyrosine kinase inhibitors including neratinib, lapatinib, poziotinib and afatinib. In particular, lapatinib, poziotinib and afatinib demonstrated comparable or stronger inhibitory ability toward the two HER2 mutants than wild type HER2 in terms of IC50. Conclusions: Our study revealed a novel class of HER2 KD indels in exon 18/19 that may act as driver mutations in several cancer types. The drug response observed in vitro indicated the potential to use anti-HER2 targeted therapies for HER2 exon 18/19 indels. Further studies on this rare type of HER2 mutation are warranted.