Venetoclax (VEN) is a BH3-mimetic drug that selectively blocks the pro-survival protein BCL2, thereby initiating cell killing in cells that are highly reliant on this pro-survival protein. Venetoclax shows remarkable clinical efficiency in treating certain blood cancers, such as chronic lymphocytic leukemia and acute myeloid leukemia. However, most patients will develop the relapsed disease while on VEN and further treatment options are then limited. My research focuses on discovering novel approaches to enhance the efficacy of VEN, such as combining VEN with immunotherapy. Therefore, it is crucial to understand how long-term VEN treatment impacts the immune cells in patients. We applied cellular indexing of transcriptomes and epitopes in single cells (CITE-seq) to peripheral blood samples from 5 patients with solid cancer before and after long-term VEN treatment, to identify heterogeneous immune subsets. CITE-seq allows us to profile the transcriptome and surface proteins simultaneously of the same cell by utilizing RNA-seq and 137 surface protein antibody-oligonucleotide conjugates. All data were integrated with harmony for batch correction and clustered based on gene expression. Pseudo-bulk analysis was then applied within cell subsets to identify consistent changes among the five patients. After VEN therapy, we found a significant depletion of most B cells, except a subset of memory B cells expressing high levels of MCL1 and BCL2A1, two pro-survival factors not targeted by VEN. In the other B-cell subsets that survived VEN treatment, we identified the upregulation of the NF-kappaB pathway. In contrast to B-cell subsets, we did not observe cell depletion or differential gene expression in T/NK-cell subsets after VEN treatment. Our data shows that VEN therapy does not directly impact T/NK cells, suggesting the potential of combining VEN with cancer immunotherapies, such as CAR-T and CAR-NK therapies.