Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples. We demonstrate that OPN-51107 induces anti-tumor activity in both CLL cell lines and patient-derived samples, including relapsed/refractory (R/R) samples and those with high-risk features (i.e. and/or deletions). Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy.