Temporal relationships among depression, medical comorbidity, and death or cardiovascular disease (CVD) events are complex. Clarifying temporal relationships may enhance current insight regarding the nature of the association of depression with poor outcomes. The temporal relation of depression symptoms (DS; score < or = 52 on five-item Mental Health Index) assessed at 6-mo intervals for 2 yr to CVD event, all-cause death, cardiovascular disease deaths, and non-cardiovascular disease deaths was studied in 917 incident dialysis patients. Cox regression models were used to assess whether the proximity of DS measurement and DS duration would change observed associations between DS and events. Whether increasing medical comorbidity was associated with worsening DS also was assessed. In time-varying models, DS were strongly associated with all-cause deaths, cardiovascular disease deaths, and CVD events (adjusted relative hazard [95% confidence interval]: 2.22 [1.36 to 3.60], 3.27 [1.57 to 6.81], and 1.68 [1.05 to 2.69], respectively). Persistent and current DS were associated with greater risks for all-cause death. Incorporating a 6-mo time lag between DS and outcomes attenuated risks for all-cause death, non-cardiovascular disease deaths, and CVD events. In a subgroup analysis, patients with worsening medical comorbidity (n = 32) during the first year of follow-up experienced a 2.42-point greater decline in mental health scores at 2 yr of follow-up compared with patients with no worsening in medical comorbidity (n = 123), but findings were not statistically significant. DS are strongly related to death and CVD events, with persistent/current DS most strongly associated with poor outcomes. Attenuated risks from time-lag analyses indicate a partial role for reverse causality, suggesting that medical comorbidity may precede DS.