BACKGROUND: Previous research has reported both a moderate degree of comorbidity between cannabis dependence and major depressive disorder (MDD) and that early-onset cannabis use is associated with increased risks for MDD. OBJECTIVE: To examine whether associations between both lifetime cannabis dependence and early cannabis use and measures of MDD, suicidal ideation, and suicide attempt persist after controlling for genetic and/or shared environmental influences. DESIGN: Cross-sectional survey of twin pairs discordant for lifetime cannabis dependence and those discordant for early cannabis use. SETTING: General population sample of twins (median age, 30 years). PARTICIPANTS: Two hundred seventy-seven same-sex twin pairs discordant for cannabis dependence and 311 pairs discordant for early-onset cannabis use (before age 17 years). MAIN OUTCOME MEASURES: Self-report measures of DSM-IV-defined lifetime MDD, suicidal ideation, and suicide attempt. RESULTS: Individuals who were cannabis dependent had odds of suicidal ideation and suicide attempt that were 2.5 to 2.9 times higher than those of their non-cannabis-dependent co-twin. Additionally, cannabis dependence was associated with elevated risks of MDD in dizygotic but not in monozygotic twins. Those who initiated cannabis use before age 17 years had elevated rates of subsequent suicide attempt (odds ratio, 3.5 [95% confidence interval, 1.4-8.6]) but not of MDD or suicidal ideation. Early MDD and suicidal ideation were significantly associated with subsequent risks of cannabis dependence in discordant dizygotic pairs but not in discordant monozygotic pairs. CONCLUSIONS: Comorbidity between cannabis dependence and MDD likely arises through shared genetic and environmental vulnerabilities predisposing to both outcomes. In contrast, associations between cannabis dependence and suicidal behaviors cannot be entirely explained by common predisposing genetic and/or shared environmental predispositions. Previously reported associations between early-onset cannabis use and subsequent MDD likely reflect shared genetic and environmental vulnerabilities, although it remains possible that early-onset cannabis use may predispose to suicide attempt.