Objective: This study examined the moderating influence of perceived social support on the prospective relationship between baseline levels of activities of daily living (ADL) and depressive symptoms during the 1st year following amputation. Method: Participants included 73 veterans with new/first unilateral lower extremity amputation due to vascular disease or diabetes. Baseline levels of perceived social support, ADL function, and mobility were assessed by retrospective recall 6 weeks after amputation. Depressive symptoms were measured at 6 weeks and 12 months following surgery. Results: Perceived social support moderated the relationship between baseline ADL functioning and depressive symptoms at 12 months (β = −0.27, p < .001) after controlling for 6-week depressive symptoms and sociodemographic and physical/functional variables. Lower levels of baseline ADL function were associated with depressive symptoms at 12 months among those who reported lower levels of perceived social support. Conclusion: These data allowed us to identify those participants with both low ADL function at baseline and low social support as being at higher risk for depression symptoms postamputation. The findings support the stress buffering hypothesis and suggest that perceived social support may be an important modifiable target of intervention among individuals with lower levels of functioning.