Chronic lymphocytic leukemia (CLL) causes early-onset immune dysregulation increasing the risk of infection, second malignancies, and autoimmune complications by poorly understood mechanisms. Targeted therapy has improved therapeutic outcomes but persistent immune deficiency remains an unresolved problem. Severe infections (20/100 patient-years) cause or contribute to over 35% of CLL-related deaths. Most identified infections are bacterial (~70%) with the commonest blood isolates being , and aureus. Viral infections (~25%) are disproportionately caused by Herpes viruses and influenza. Most common infection sites are lower respiratory tract, skin, and urogenital tract. CLL patients have an increased risk (~2-fold) of second malignancies with the commonest being squamous and basal cell skin cancer, melanoma, and lung cancer. There is a significantly increased risk of additional clonal and non-clonal non-Hodgkin lymphomas and Hodgkin lymphoma. Autoimmune cytopenias affect ~10% of CLL patients causing anemia (hemolysis and red cell aplasia), thrombocytopenia, and neutropenia. Nonhematological autoimmune complications are rare. Management of these complications requires a comprehensive multidisciplinary approach including education, preventative medicine, active monitoring, and early diagnosis and treatment. Research to better understand CLL-related immune defects and determine how to reverse them is essential for improved clinical care.