Although a species of conservation concern, little is known about the reproductive success of Least Terns (Sternula antillarum) throughout the southeastern USA where availability of natural beaches for nesting is limited. Daily survival rate (DSR) of nests and chicks was examined at four natural nesting sites in Cape Romain National Wildlife Refuge, South Carolina, 2009–2010. Measures of nest success (n = 257 nests) ranged from 0–93% among colony sites. The DSR of nests was primarily related to colony site, but year and estimates of predation risk also were related to DSR. Predation was the principal cause of identifiable nest loss, accounting for 47% of nest failures when the two years of data were pooled. The probability (± SE) of a chick surviving from hatching to fledging = 0.449 ± 0.01 (n = 92 chicks). DSR of chicks was negatively related to tide height and rainfall. Therefore, productivity of Least Terns is being lost during both the nesting and chick stage through a combination of biotic and abiotic factors that may prove difficult to fully mitigate or manage. Although natural nesting sites within Cape Romain National Wildlife Refuge intermittently produce successful nests, the consistency of productivity over the long term is still unknown. Given that the long term availability of anthropogenic nest sites (e.g., rooftops, dredge-spoil islands) for Least Terns is questionable, further research is required both locally and throughout the region to assess the extent to which natural sites act as population sources or sinks.