Purpose: To assess the relationship between nocturnal plasma melatonin and serum estradiol (E 2 ) and progesterone (P 4 ) levels in depressed pregnant women (DW) and matched healthy women (HW). Methods: We used analysis of variance (ANOVA) and linear regression analyses on data obtained from pregnant HW and DW. Results: Log E 2 and log P 4 were positively correlated with measures of melatonin quantity in HW ( p < 0.05) but not DW, controlling for age. Log E 2 and log P 4 were positively correlated with melatonin offset and duration in DW ( p < 0.01) but not HW. Conclusions: Pregnant DW may be less sensitive than HW to modulation of melatonin secretion by E 2 and P 4 . That melatonin timing measures are more sensitive to E 2 and P 4 variation in DW may reflect a circadian system more attuned to the need for realignment in DW than in HW. These altered sensitivities to reproductive hormones may reflect a biologic vulnerability that predisposes some pregnant women to depression.