Here we show that maternal smoking downregulated, in a dose-dependent manner, cytotrophoblast expression of l-selectin and its TRA-1-81-reactive carbohydrate ligands. Cell islands -- cell columns that fail to make uterine attachments, often more numerous in the placentas of smokers -- exhibited an even greater downregulation of the l-selectin adhesion system. These effects were attributable to nicotine, since exposure of explanted villi to this drug in vitro reproduced the effects observed in situ. Videomicroscopy showed that the downstream consequences included inhibition of all stages of cytotrophoblast outgrowth from columns, including rolling adhesion within columns and generation of invasive cells at the distal ends. These results suggest that nicotine, acting through the l-selectin adhesion system, impairs the development of cell columns that connect the fetal portion of the placenta to the uterus, one possible reason why women who smoke have a much harder time achieving and sustaining pregnancy than their nonsmoking counterparts.