This study assessed whether the route of administration of estrogen had an effect on serum amyloid A (SAA) and the SAA content of high-density lipoprotein (HDL-SAA) levels in post-menopausal women. A group of 29 women were randomised to receive transdermal estradiol (100 µg daily), synthetic conjugated estrogen (0.625 mg daily) or a placebo for 8 weeks. There was an increase in total SAA (by 20%) and HDL-SAA (by 10%) levels in the group receiving oral estrogen. This was compared to a significant decrease by 25% in both SAA and HDL-SAA levels for the transdermal estradiol group. The placebo had no effects on these levels. These findings are clinically significant considering that elevated SAA levels interfere with the antiatherogenic, antioxidative and anti-inflammatory properties of HDL. SAA is also a precursor of amyloid fibroid which deposits in the brain of Alzheimer’s disease patients. In addition, elevated SAA levels are independently associated with adverse cardiovascular events in women.