Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered ‘unfit’ for fludarabine–cyclophosphamide–rituximab therapy. In these patients, the combination of obinutuzumab–chlorambucil may be an appropriate therapeutic choice. Obinutuzumab–chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab–chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab–chlorambucil.