Aim: To investigate interactions of gold nanoparticles with primary human lymphocytes and determine if the addition of a self-assembled monolayer of ‘mixed-matrix’ ligands influenced these interactions. Materials & methods: The effect of gold nanoparticles was measured by exposure to peripheral blood mononuclear cells (PBMCs) from healthy volunteers with subsequent examination of cell proliferation, cytokine secretion and CD4⁺ T-cell activation relative to controls. Results: Capped and as-synthesized gold nanoparticles augmented PBMC proliferation in response to phytohemagglutinin and this effect was greater for as-synthesized than for capped gold nanoparticles. Release of IL-10 and IFN-γ from PBMCs was increased and the effect was again more marked for as-synthesized than capped gold nanoparticles. Conclusion: This method provides an ex vivo approach for studying the interaction of nanoparticles with the human immune system. Further research is required to determine the specific mechanisms for reduction of immune activation seen here which could then be used to design a truly ‘stealth’ nanoparticle. Original submitted 11 October 2013; Revised submitted 30 January 2014