This 18-month follow-up study examined the predictors of the severity of depressive symptoms among intravenous heroin users receiving methadone maintenance treatment (MMT) in Taiwan. The severity of depressive symptoms in 368 intravenous heroin users receiving MMT in southern Taiwan was assessed using the Center for Epidemiological Studies Depression scale at baseline and at 3, 6, 9, 12, 15, and 18 months of treatment. Demographic and substance-using characteristics, severity of heroin use, HIV serostatus, criminal record, and family function were collected during baseline interviews. Data on methadone dosage at each follow-up interview and the duration of retention in the MMT program were also collected. A generalized estimating equation was used to determine independent predictors of depressive symptoms during the 18-month period of MMT. Female gender, lack of fixed employment, severe heroin use, concurrent methamphetamine use, low family function at baseline, heroin use during the MMT, low methadone dosage, and short duration of participation in MMT predicted more severe depressive symptoms during the 18-month MMT. This study found that sociodemographic and substance-using characteristics at baseline predicted the severity of depressive symptoms among heroin users receiving MMT. Methadone dosage and MMT duration were also predictive of depression severity. The predictors found in this study can be used to identify heroin users who are at risk for depressive symptoms in the MMT program.