Here, we examined both genetic and phenotypic determinants of nurse-like cells (NLCs) to better predict their putative functions in chronic lymphocytic leukemia (CLL). We showed that NLCs belong to the wound-healing macrophage subset (so-called 'M2 subset'), but most of all, unsupervised clustering analysis positions NLCs as CLL-specific tumor associated macrophages (TAMs). Chemokinome assays confirmed that NLCs secrete prototypical M2 cytokines and chemokines. Extending previous reports of fludarabine resistance, NLCs are able to promote multidrug resistance. Altogether, we propose that NLCs are not just nursing, but actively participate in the setting of an environment-mediated drug resistance (EM-DR) and immune escape for CLL cells.