The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and a preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation level-dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) in the right middle temporal/angular gyrus while subjects were viewing negative versus neutral words. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared with controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared with controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 single nucleotide polymorphism rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.