Altered Doppler flow velocimetry of the uterine arteries during the second trimester is correlated with the risk of developing pre-eclampsia. Serum levels of leptin, a protein regulating body weight and secreted by the placenta, are higher in women with severe pre-eclampsia. We investigated whether alterations of uterine arteries' Doppler flow velocimetry during the early second-trimester scan were accompanied by changes in leptin levels, and whether these changes might be an early risk factor for pre-eclampsia. We retrospectively selected 50 women with altered uterine artery velocimetry at the second-trimester scan who subsequently developed pre-eclampsia (group A) and 100 women who did not develop pre-eclampsia, divided into two groups: 50 women with normal velocimetry at the second-trimester scan (group B) and 50 women with altered velocimetry at the second-trimester scan (group C). Serum leptin levels during the second and third trimesters and bilateral uterine artery resistance index during the second trimester were evaluated. No differences were observed in serum leptin levels in the second trimester among the three groups. During the third trimester, women in group A showed significantly higher serum leptin levels in comparison with women in groups B and C (p < 0.01). Serum leptin levels do not seem to be a useful early marker for the development of pre-eclampsia in the presence of altered uterine blood flow, and may be a late compensatory mechanism or reflect a generalized response of the trophoblast to hypoxic stimuli.