Monoclonal antibodies (mAbs) are increasingly being used in the treatment of cancer. One limitation of mAbs however, is highly variable and unpredictable pharmacokinetics between individuals and sexes that can potentially impact on therapeutic success and the severity of adverse effects. There is therefore a need to identify the underlying source of inter-individual and sex-based differences in mAb pharmacokinetics. Moreover, it would be useful to identify pharmacokinetic sex differences and the source of inter-individual variability at the preclinical stage in rodents, so that more informed human clinical trials can be designed. This study aimed to evaluate 1) whether rats can be used as a model to identify non-antigen related mAb pharmacokinetic sex-differences in humans, and 2) if the underlying source of inter-individual and inter-sex pharmacokinetic differences can be identified in rats. The anti-EGFR antibody cetuximab was used as a model mAb, since it exhibits 25% lower plasma clearance in women. Cetuximab was intravenously administered to age- and litter-matched male and female rats. Blood samples were serially collected for up to 1.5 months. Pharmacokinetic parameters were correlated with pre-dose physiological variables, including fat-free mass, peripheral white cell and monocyte counts, liver and spleen biodistribution, and plasma sex hormone, albumin and IgG concentrations, to identify possible sources of pharmacokinetic variability. Pharmacokinetic sex-differences observed in humans were not seen in rats, but a high degree of inter-individual variability was observed. Plasma clearance negatively correlated with monocyte count and spleen biodistribution, and positively correlated with albumin, but not with any other parameters. Therefore, while rats are not an appropriate pre-clinical model for identifying sex-based differences in mAb pharmacokinetics, they may be used to evaluate inter-individual variability. Further, these results suggest that antibody recycling pathways in monocytes (ie. FcRn) overcome degrading (ie. FcγR) pathways in rats and that this, together with the propensity for splenic distribution, can drive the pharmacokinetic differences observed in rats. This finding requires closer investigation in both isolated rat and human monocytes.