Background: Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family and a key oncogene in solid tumors. Pyrotinib has been approved for the treatment of HER2-positive, recurrent or metastatic breast cancer. However, there are very few clinical studies on pyrotinib in other HER2-positive solid tumors. Therefore, more clinical evidence is urgently needed to guide pyrotinib-based therapy in HER2-positive non-breast advanced solid tumors. Methods: We retrospectively analyzed HER2-positive non-breast advanced solid tumors patients with HER2 amplification or mutations who were treated with pyrotinib-based therapy in Henan Cancer Hospital between July 1, 2019 and December 2, 2021. In this study, 25 eligible patients were included with 16 patients with lung cancer, 6 with gastric cancer, 2 with colorectal cancer and 1 with cholangiocarcinoma. The primary end point was progression-free survival (PFS). Results: The median PFS and overall survival (OS) were 188 days (95% CI: 83–NA days) and 250 days (95% CI: 188–NA days), respectively. 16 patients with lung cancer and 6 patients with gastric cancer had a median PFS of 204 days (95% CI: 55–NA days) and 142 days (95% CI: 83–NA days), respectively. The median OS was 366 days (95% CI: 248–NA days) in patients with lung cancer and 179 days (95% CI: 90–NA days) in patients with gastric cancer. Patients receiving > 3 lines of therapies had a numerically lower median PFS and OS than those receiving≤ 3 lines of treatments (PFS:188 vs 204 days, p=0.92; OS:188 vs 366 days, P = 0.43). All 25 patients were available for efficacy evaluation. The objective response rate (ORR) was 24% and disease control rate (DCR) was 68%. The ORR for lung cancer was 25% and for gastric cancer was 16.7%. In addition, the DCR for lung cancer was 62.5% and for gastric cancer was 66.7%. Moreover, patients receiving≤3 lines of treatments had a numerically higher ORR and DCR than those receiving >3 lines of treatment (ORR:35.7% vs 9.1%,p=0.18; DCR:71.4% vs 63.6%, P＞0.99). The most common treatment-related adverse events (TRAEs) were diarrhea (84%), but only 3 (12%) patients reported grade 3 diarrhea which could be well controlled. Conclusions: These results indicated that pyrotinib-based therapy exhibited good anti-tumor activity and acceptable safety profile in HER2-positive non-breast advanced solid tumors. This retrospective study is a pilot study aimed at promoting larger-scale studies to further clarify the safety and efficacy of pyrotinib in the treatment of non-breast solid tumors. Keywords: pyrotinib, HER2-positive, solid tumor, retrospective study, advanced solid tumors.