Monoclonal antibodies (mAbs) are increasingly being used to treat a range of cancers. Some mAbs however, exhibit significant pharmacokinetic sex differences that have not been mechanistically explained. To this end, mAbs have previously been shown to exhibit significant lymphatic exposure after intravenous administration. We therefore sought to examine whether the lymphatic exposure of cetuximab (anti-EGFR mAb; Erbitux) differed between male and female rats. Litter-matched SD Rats were cannulated via the right carotid artery, the right jugular and the thoracic lymph to allow the continuous collection of lymph fluid. Rats were dosed with 4 mg/kg cetuximab intravenously and lymphatic pharmacokinetics evaluated over 30 h. Results were compared to rats that had an intact (uncannulated) thoracic duct. While no significant sex differences were observed in the plasma pharmacokinetics of lymph-intact rats, female rats cannulated via the thoracic lymph duct exhibited two-fold higher lymphatic uptake compared to male rats. This observation occurred in the absence of a significant difference in lymph flow rates. In support of the observations of higher lymphatic exposure in lymph duct cannulated animals, the lymph node biodistribution of cetuximab was also significantly higher in lymph-intact rats 7 days after IV dosing. The presence of a sex-based difference in the lymphatic exposure of cetuximab in the absence of a sex-based difference in plasma pharmacokinetics suggests that differences in lymphatic trafficking do not impact on plasma concentrations in healthy individuals with an intact lymph-blood circuit. Rather, the data may suggest that females exhibit leakier vasculature than males, and that the lymphatic system simply functions to recirculate extravasated antibody back to the blood and maintain high vascular antibody exposure. Further, since mAbs (including trastuzumab) are already known to display good lymphatic exposure after intravenous dosing, the plasma clearance of mAbs may be significantly higher in individuals with a compromised lymph-blood circuit, such as in women who have undergone extensive lymphadenectomy for breast cancer. This warrants further clinical investigation.