The assumption that depressed patients who are assigned to placebo in antidepressant clinical trials are exposed to substantial morbidity and mortality has not been based on research data. Because of worldwide concern about placebo use and the implications of our earlier findings of no increased suicide risk in placebo-treated patients, we conducted a replication study in a new patient sample. We assessed suicide risk and symptom reduction among placebo-treated patients participating in antidepressant clinical trials for two recently approved antidepressants, venlafaxine ER and citalopram, which were unavailable during our previous study. Among 23,201 participant patients, 32 committed suicide and 172 attempted suicide. Rates of suicide and attempted suicide did not differ significantly among the placebo- and drug-treated groups. Based on patient exposure years, annual rates of suicide and attempted suicide were 0.5 and 6.7% with placebo, 0.9% with active comparator (rates for attempted suicide are unavailable), and 0.6 and 6.3% with investigational antidepressants. Symptom reduction was 47.9% with investigational drugs (n = 1172), 47.5% with active comparators (n = 161), and 35.5% with placebo (n = 606). These data may inform discussions about the use of placebo in antidepressant clinical trials.