Crucial for CLL development and progression are iterative cycles of cell re-activation and proliferation in lymphoid tissues. Since cellular fatty acid (FA) import and oxidation (FAO) were recently reported to be upregulated in CLL, we explored in-vitro effects of ST1326, a reversible inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), on leukemic cells subject to activating microenvironment-mimicking stimuli. ST1326 induced dose-dependent mitochondrial dysfunction and cell death, which were remarkably higher in activated/proliferating than quiescent CLL cells. Drug sensitivity was observed irrespective of the presence of TP53 alterations or chromosomal abnormalities. ST1326 cytotoxicity was associated with decreased levels of intracellular acetylCoA and phosphorylated STAT3, known to favor CLL cell proliferation and upregulate antiapoptotic Bcl-2 family members. Indeed, rising of Mcl-1 and Bcl-xl expression in response to microenvironment stimulation was impaired by ST1326. Drug combination experiments with the BH3-mimetic ABT-199/Venetoclax, whose effects are counteracted by Mcl-1/Bcl-xl and cell proliferation, showed strong ST1326-mediated potentiation of ABT-199 cytotoxicity in activated/proliferating CLL cells. The data indicate that CLL cells turning to an activated/proliferating state become more dependent on FAO and more sensitive to FAO-antagonists, and pave the way for ST1326 as an adjuvant tool in anti-CLL drug-combination regimens with drugs that loose efficacy on proliferating leukemic cells.