This study investigated the prospective links of negative life events and parent-child closeness with depressive symptoms among siblings using a multilevel modeling approach with a genetically informative design. The sample consisted of 756 adolescents (378 sibling pairs) who participated in two waves of the Nonshared Environment in Adolescent Development Project. Sibling pairs with varying degree of genetic relatedness (i.e., monozygotic, dizygotic, full siblings, half siblings, and genetically unrelated siblings) were included. The results showed that negative life events, both personal and family life events, and parent-child closeness at Time 1 were significantly associated with depressive symptoms at Time 2 after accounting for the intrapair correlations between siblings. The effects remained significant after controlling for the levels of preexisting depressive symptoms. More importantly, closeness with mothers, but not with fathers, moderated the effects of both personal and family negative life events on subsequent depressive symptoms.