We assessed whether, after controlling for genetic and shared environmental influences, early cannabis use remains a significant predictor of other drug use, abuse, and dependence, and whether the risk for early-users is greater than that for later cannabis users. Data from a 1992 telephone diagnostic interview of 8169 male twins (M=42.0 years at interview) who served in the U.S. military during the Vietnam-era were used to identify a subsample of 293 monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for early cannabis use (before age 18). Using cotwin-control analyses, outcomes assessed were: lifetime illegal drug use (stimulant/cocaine, sedative, opiate, and hallucinogen/PCP), lifetime DSM-III-R illegal drug abuse/dependence, and lifetime DSM-III-R alcohol dependence. After controlling for covariates, early cannabis users were at greater risk than their later/never-using cotwins for 8 of 9 substance-related comparisons, including: using other illegal drugs (ORs: 2.71-4.09), having illegal drug abuse/dependence (ORs: 2.02-2.13), and developing alcohol dependence (OR=2.36). When analyses were limited to pairs in which the cotwin used cannabis later, early and later-users only differed significantly on sedative, opiate, and hallucinogen use. After familial influences on early cannabis use were controlled for, cannabis use-regardless of the age of initiation-still conferred increased risk of other illegal drug use, drug abuse/dependence, and alcohol dependence. In contrast to previous research, there is limited evidence for increased risk associated with early-onset use in this sample of Vietnam-era veterans.