OBJECTIVES:  Chronic lymphocytic leukaemia (CLL) is the most common type of chronic leukaemia, and mostly occurs in people aged ≥60 years. Ofatumumab is an anti-CD20 monoclonal antibody currently approved as a targeted therapy for CLL. This systematic review aims to assess the safety and efficacy of ofatumumab as a combination therapy, compared to other treatment regimens in CLL patients, irrespective of disease status. METHODS:  Randomised controlled trials (RCTs), which included ofatumumab as a combination intervention for previous untreated, relapsed or refractory CLL, were identified from 2006 to 2016 in databases such as, Cochrane, and PubMed. Relevant conference abstracts and posters were also hand searched. Two researchers independently reviewed studies using the Cochrane methodology for systematic reviews. Outcomes of interest included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety. RESULTS:  In total, 292 potentially relevant studies were screened. Three RCTs involving 1073 patients with CLL met the inclusion criteria; where 578 patients were randomised to receive a combination treatment (ofatumumab in combination with chlorambucil, or idelalisib, or fludarabine and cyclophosphamide), and 495 patients were to receive other mono- or chemotherapy drugs. Results were not pooled due to clinical heterogeneity with the limitation of only one trial for each combination therapy. Overall, all ofatumumab combinations significantly improved PFS and OS in CLL patients, including those with adverse prognostic characteristics, with tolerable adverse events (AEs). The ORR was higher in patients assigned to a combination therapy with ofatumumab than in other treatment regimens. The safety profile of ofatumumab, including the incidence of Grade ≥3 AEs, was comparable to all other interventions. CONCLUSIONS:  Ofatumumab is an important treatment option for elderly patients with CLL. However, even when trials have significant outcomes, the results have to be interpreted cautiously due to the limited number of trials for each combination therapy.