Background: Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (MBC) are usually treated with endocrine therapy (ET) in combination with cyclin dependent kinase (CDK4/6) inhibitors. Such combinations have significantly improved treatment outcomes. HER2-negative MBC have recently been divided into two subgroups: HER2-zero, with an immunohistochemistry (IHC) score of 0, and HER2-low, with an IHC score of 1+ or 2+ and a negative in situ hybridization (ISH) assay. The aim of this meta-analysis is to compare treatment outcomes of these two groups of MBC patients when treated with a combination of ET and CDK4/6 inhibitors. Methods: A systematic literature review was conducted to identify relevant studies on the level of HER2 expression in breast cancer patients treated with CDK4/6 inhibitors. The review included articles in databases such as Medline via PubMed, Embase, and Cochran Library, as well as abstracts from the ASCO meeting and SABCS conference updated tell January 2023. Eligible studies included randomized controlled trials, prospective or retrospective studies, and case-control studies that compared the difference in PFS between HER2-low and HER2-zero among breast cancer patients treated with CDK4/6 inhibitors in first-line or beyond setting. A meta-analysis was performed to determine the pooled hazard ratio for progression-free survival (PFS). In addition, a pooled survival curve was created by digitizing the Kaplan-Meier curves to create pseudo-individual patients’ data following the methodology outlined by Combescure et. al (2014). Results: In total, 7 different studies were identified that included a total of 1,341 patients. The random effect model shows a statically significant shorter PFS in the HER2-low group; 17.2 months compared to 24.0 months in HER2-zero group (HR=1.55; 95% CI [1.27-1.84]; p <0.001). There was no statically significant heterogeneity between the studies (I²=51% p-value=0.07). The PFS rates at 12, 24, 36, and 48 months for HER2-low were as follow: (66.2%; 95% CI [50.0%-87.5%]), (33.2 %; 95% CI= 17.4%-63.4%), (26.2%; 95% CI= 12.8%-53.38%), and (22.05%; CI95%= 10.32%-47.12%), respectively compared to: (77.73%; 95% CI= 64.45%-93.75%), (50.00%; 95% CI= 34.66%-72.13%),(43.58%; 95% CI= 22.91%-82.89%), and (36.85%; 95% CI= 17.60%-77.15%) among patients with HER2-zero. Conclusions: In patients with MBC treated with CDK4/6 inhibitors, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better PFS compared to those with HER2-low disease. Such findings, if confirmed in larger studies, may change the landscape of treatment of this group of patients.