Ingested, inhaled or injected particles come into contact with biological fluids containing polymers, such as the protein fibrinogen. We studied interactions between well-characterized submicron particles or nanoparticles (NPs) and human fibrinogen. In vitro aggregation and zeta potential measurements of different sized and functionalized polystyrene, carbon black and silica NPs suspended in fibrinogen solutions were made. Particle size, surface charge and aggregation behaviour significantly changed in the presence of fibrinogen. Polymer (protein) bridging and bridge flocculation was observed. We concluded: (1) NP aggregation rate in a fibrinogen solution depended on particle surface type; (2) amine-functionalized particles aggregated more slowly in fibrinogen; and (3) particle morphology strongly influenced biologically available surface for protein attachment, but this did not correlate well with particle surface area for complex particles (calculated or measured). Interaction of particles and NPs with pro-coagulant polymers may therefore dictate the NP surface dose presentation to cells/organs and subsequent cellular effects, in and ex vivo.