Early-onset methamphetamine use increases the lifetime prevalence of methamphetamine dependence. An earlier onset of methamphetamine use leads to greater damage to the terminal ends of serotonin neurons, more reduction in serotonin transporter (5-HTT) density, and an increased propensity toward further methamphetamine use. Because genetic variation within the promoter region of the 5-HTT gene (the 5-HTT-linked polymorphic region; 5′-HTTLPR) leads to differential expression of the 5-HTT, we examined, for the first time, whether this could be a candidate site associated with predisposition toward early-onset methamphetamine use. We sought to determine whether there is a differential association between the long (L) and short (S) polymorphic variants of the 5′-HTTLPR and the age of first methamphetamine use. The study included 36 of 150 methamphetamine-dependent subjects enrolled in a multi-site, double-blind, randomized, placebo-controlled clinical trial. DNA was extracted from the blood samples of 36 subjects who consented to this genetic study. Diagnosis of methamphetamine dependence and age of first methamphetamine use were collected using structured questionnaires. Genotype in the 5′-HTTLPR was determined individually for each subject, and their associations with the age of onset of methamphetamine use were analyzed. Individuals with the LL genotype compared with S-carriers in the 5′-HTTLPR had more than a 3 times greater risk of an earlier onset of methamphetamine use (hazard ratio=3.27; 95% confidence interval=1.26–8.50; p=0.01), where onset occurred about 5 years earlier (p=0.04). LL genotype in the 5′-HTTLPR may be associated with an increased risk of early-onset methamphetamine use among methamphetamine-dependent individuals.