BACKGROUND The widely accepted impression that substance abuse and dependence are associated with increased suicidal risk was evaluated by literature review and with new data. METHODS Previous research on this association was reviewed, and clinical data on suicide attempts and substance use in 504 mood disorder patients hospitalized in 4 psychiatric units in Sardinia affiliated with the Italian mental health system were analyzed. RESULTS The literature supports associations of alcohol and drug use comorbidity with major affective disorders, and of some substances (polyabuse, alcohol, heroin, cocaine, and even tobacco, but perhaps not marijuana or hallucinogens) with suicidal behavior. Our new findings generally supported these 2-way associations. Suicidal risks were similar in hospitalized men and women but were associated with bipolar II, bipolar I (mainly mixed), and unipolar depressive disorders as well as substance abuse, with little effect of type of agent. Substance abuse was more common in nonmixed bipolar disorders, men, and age below 30. CONCLUSIONS The tendency for bipolar I, mainly nonmixed patients, to have a relatively high risk of substance abuse and low risk of suicide attempts indicates that mainly depressive or dysphoric (bipolar II, nonbipolar, and bipolar I, mainly mixed) mood disorders may be especially lethal. Differences in risks of substance abuse and suicidal behavior in men and in bipolar I patients further suggest that substance abuse and mood disorders may contribute to suicidal risk with at least partial independence or additivity.