PEGylated liposomal doxorubicin (Caelyx) has been reported to show high and unpredictable inter-individual pharmacokinetic variability and two-fold faster clearance in <60 year old males compared to females. Currently however, these observations are mechanistically unexplained. The aim of this study was to determine whether healthy rats can be used as a model to identify the source of inter-individual and sex-based pharmacokinetic differences in Caelyx pharmacokinetics by following the structural lipids as well as the loaded drug (Dox). Male and female Sprague Dawley rats (n=5 each) were dosed 2 mg/kg Caelyx (as Dox) IV, as well as the 3H-labelled non-drug loaded liposome to evaluate the pharmacokinetic behaviour of the structural phospholipid. Blood, urine, and faeces were serially sampled over 5 days and major organs were harvested on day 5. Potential predictive biomarkers of Caelyx pharmacokinetics (body weight, fat free mass, peripheral monocyte and white cell count, plasma estrogen, testosterone, albumin, α1 acidic glycoprotein and IgG) were evaluated prior to Caelyx dosing. Dox was cleared 1.4-fold faster in male compared to female rats but no sex differences were apparent in 3H-liposome clearance. This suggested that males and females exhibit differences in Dox release kinetics, but not liposome clearance. Male and female rats showed no significant difference in urinary excretion of 3H-liposome, and none of the biomarkers examined correlated with Dox or 3H-liposome clearance. Females exhibited higher biodistribution towards the liver and lymph nodes on a per mass basis, but not on a whole organ basis. These data suggested that while sex-based differences exist in loaded Dox (but not liposome) clearance in healthy rats, they are not of the same magnitude as that reported in humans. However, retrospective statistical evaluation of published pharmacokinetic data in humans revealed that significant sex differences in Caelyx pharmacokinetics are only apparent in HIV affected patients with Kaposi’s sarcoma. This suggests that immune status likely plays an important role in Caelyx pharmacokinetics and warrants further investigation.