IMPORTANCE Various neuropsychiatric disorders, especially addictions, feature impairments in risky decision making; clarifying the neural mechanisms underlying this problem can inform treatment. OBJECTIVE To determine howmethamphetamine-dependent and control participants differ in brain activation during a risky decision-making task, resting-state functional connectivity within mesolimbic and executive control circuits, and the relationships between these measures. DESIGN, SETTING, AND PARTICIPANTS A case-control, functional magnetic resonance imaging study of methamphetamine-dependent and healthy comparison participants at rest and when performing the Balloon Analogue Risk Task, which involves the choice to pump a balloon or to cash out in the context of uncertain risk. Conducted at a clinical research center at an academic institution, this study involved 25 methamphetamine-dependent and 27 control participants. MAIN OUTCOMES AND MEASURES Parametric modulation of activation in the striatum and right dorsolateral prefrontal cortex (rDLPFC; ie, the degree to which activation changed as a linear function of risk and potential reward), both indexed by pump number, and resting-state functional connectivity, measured in the whole brain with seeds in the midbrain and rDLPFC. Relationships between these outcomes were also tested. RESULTS Parametric modulation of cortical and striatal activation by pump number during risk taking differed with group. It was stronger in the ventral striatum but weaker in the rDLPFC inmethamphetamine-dependent participants than control individuals. Methamphetamine-dependent participants also exhibited greater resting-state functional connectivity of the midbrain with the putamen, amygdala, and hippocampus (P < .05, whole brain, cluster corrected). This connectivity was negatively related to modulation of rDLPFC activation by risk level during risky decision making. In control participants, parametric modulation of rDLPFC activation by risk during decision making was positively related to resting-state functional connectivity of the rDLPFC with the striatum. CONCLUSIONS AND RELEVANCE Maladaptive decision making bymethamphetamine users may reflect circuit-level dysfunction, underlying deficits in task-based activation. Heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, may create a bias toward reward-driven behavior over cognitive control in methamphetamine users. Interventions to improve this balance may enhance treatments for stimulant dependence and other disorders that involve maladaptive decision making. © 2014 American Medical Association. All rights reserved.