Despite the considerable progress in the chronic lymphocytic leukaemia (CLL) therapy, relapse or progression to a Richter syndrome still appears. Thus, a more targeted therapeutic option is required. This can be achieved by increasing the concentration of the cytostatic drug in the tumour while reducing its systemic toxicity. In the continuous effort toward the development of more efficient therapeutics, in the current study we report rituximab conjugated gold nanoparticles for CLL treatment. The formation of rituximab-nanoconjugates was proved by physico-chemical characterization (UV-Vis spectroscopy, zeta potential and dynamic light scattering) and their intracellular internalization was assessed by dark field and transmission electron microscopy. The therapeutic effect of the newly-designed drugs was investigated by cell counting and MIT assays. Results showed that the effect of our drug-nanocarrier is superior compared to that of the drug alone, data confirmed by state-of-the-art analyses of internalization, cell biology (flow cytometry, apoptosis and autophagy assay), genomics (RT-PCR for MS4A1) and proteomics (confocal microscopy and western blotting for CD20). The present work demonstrates that rituximab nanoconjugates can get an efficient trans-membrane delivery inside CLL cells, being validated as real-potential therapeutics with increased efficacy compared to the drug alone.