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Introduction Cyclin-dependent kinase (CDK) 4/6 inhibitors represent a new paradigm in the treatment of hormone receptor (HR) positive and HER-2 negative metastatic breast cancer (MBC). However, despite their evident clinical benefit, the cellular and molecular mechanisms underlying treatment efficacy and drug failure are still largely unknown. CDK4/6 inhibitors block the cyclin D1-CDK4/6 interaction, leading to inhibition of cell cycle progression through the G1/S phase and inhibiting cell proliferation. SAMHD1 is a dNTPase that maintains the intracellular dNTP pool at levels adequate for DNA replication and repair. SAMHD1 function is regulated by phosphorylation, a process controlled by CDKs. Moreover, SAMHD1 has also been shown to modify the efficacy of different nucleotide analogues. Here, we aim to evaluate the capacity of selective CDK4/6 inhibitors to modify the efficacy of different antimetabolites currently used for cancer treatment. Material and methods: Cytotoxic activity of 5-fluorouracil, its prodrug capecitabine and the anti-folate pemetrexed was evaluated alone or in combination with the CDK4/6 inhibitor palbociclib in breast cancer cell lines (T47D and MDA-MB-468) and primary cells expressing or not SAMHD1 through HIV-2 Vpx mediated degradation. Cytotoxicity was measured either by colorimetric tetrazolium dye MTT method or flow cytometry. Drug combinations were evaluated by calculating the combination index (CI) through the ixobologram equation, considering a synergic drug combination a CI Citation Format: Eudald Felip, Roger Badia, Mireia Margeli, Marc Castellvi, Vanesa Quiroga, Iris Teruel, Beatriz Cirauqui, Margarita Romeo, Ifeanyi Jude Ezeonwumelu, Eva Riveira-Munoz, Jose Este, Ester Ballana. Cyclin-dependent kinases inhibitors improve antimetabolite drug potency depending on SAMHD1 expression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-14.