Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n = 70) of 14-year olds with a history of cannabis use to a group (n = 70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood. ; This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the FP7 projects IMAGEMEND (602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), a Medical Research Council Programme Grant “Developmental pathways into adolescent substance abuse” (93558), the Swedish funding agency FORMAS, the Medical Research Council and the Wellcome Trust (Behavioural and Clinical Neuroscience Institute, University of Cambridge), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministerium für Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc 01ZX1311A; Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG): Reinhart-Koselleck Award SP 383/5-1 and grants SM 80/7-1, SFB 940/1, FOR 1617), the French MILDT (Mission Interministé rielle de Lutte contre la Drogue et la Toxicomanie), the CENIR (Centre de NeuroImagerie de Recherche, Pr. S. Lehéricy) within the ICM institute, the National Institute of Mental Health (MH082116), and a National Institutes of Health Center of Biomedical Research Excellence award P20GM103644 from the National Institute of General Medical Sciences. HG was supported, in part, by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. We thank Jackson Mathews for his assistance on figures and references.