Background: HER2-Low breast cancer (BC) has been recently identified as a new therapeutic target. However, it is unclear if HER2-Low status has an independent impact on prognosis, both in metastatic and early settings. Methods: A systematic literature research of PubMed, Cochrane and conference proceedings (ASCO meetings, SABCS and ESMO congress) up to December 8, 2022 was performed to identify studies comparing survival outcomes of patients affected by HER2-Low BC vs. HER2-zero BC. HER2-Low status was defined as immunohistochemistry score 1 + or 2+ without in situ hybridization amplification. Pooled hazard ratios (HRs) for survival endpoints in the metastatic [progression-free survival (PFS), overall survival (OS)] and in the early [disease free-survival (DFS) and OS] settings as well as their 95% confidence intervals (95%CI) were calculated using the random-effect model of Der Simonian and Laird. The above-mentioned endpoints were also assessed according to estrogen receptor (ER) status. Results: Among 1,916 identified records, 42 studies including 1,797,377 patients were eligible for this analysis. We show the pooled HRs in the overall population and specific subgroups. In the early setting, HER2-Low status was associated with significant improved DFS (HR 0.86, 95%CI 0.79-0.92, p<0.001) and OS (HR 0.84, 95%CI 0.77-0.92, p<0.001) when compared to HER2-zero status. Improved OS was observed in subgroup analysis for both ER-positive and ER-negative HER2-Low populations, while DFS improvement was observed only in the ER-positive subgroup. Similarly, in the metastatic setting, patients affected by HER2-Low BC showed better OS when compared to those with HER2-zero BC (HR 0.94, 95%CI 0.89-0.98, p=0.008). HER2-Low metastatic BC was associated with significant improvement in OS compared to HER2-zero BC also in ER-positive and ER-negative subgroups. No significant differences were found in terms of PFS. Conclusions: Compared with HER2-zero status, HER2-Low status appears to be associated with an increased OS both in the advanced and early settings, regardless of hormone-receptor expression.