Purpose The research questions of the present study were: (1) Is total knee prosthesis wear behaviour influenced by implant size, body weight and their combined effect? (2) Are these findings significant and helpful from a clinical point of view? Methods Two very different sizes of the same total knee prosthesis (TKP), previously tested with ISO 14243 parameters, were tested on a knee simulator for a further two million cycles using a modified ISO 14243 load waveform. Roughness examination was performed on the metallic components. Gravimetric and micro-Raman spectroscopic analyses were carried out on the polyethylene inserts. Results The average volumetric mass loss was 69 ± 3 mm 3 and 88 ± 4 mm 3 for smaller and bigger size, respectively. Bigger TKPs are little influenced by an increased load, while the wear trend of the smaller TKP showed a redoubled slope, and more significant morphology changes were observed. However, the two sizes seem to behave similarly when subjected to a load increase of 15 %; the slope of the volumetric mass loss trend was comparable for the two sets of inserts, which did not appear significantly different also at the molecular level. Roughness average parameters of the lateral femoral condyle support this evidence. Conclusions It can be asserted that the body weight and implant size are relevant to the understanding of TKP wear behaviour. A post-implantation body weight increase in a patient with smaller knee dimensions could results in more critical effects on prosthesis long-term performance.