One paradigmatic example of “irrational” bias in human economic decision-making—known as the “reflection effect”—is a tendency to prefer sure amounts over risky gambles in situations involving potential gain, but to prefer risky gambles over sure amounts in situations involving potential loss. To date, there is no causal evidence regarding the neural basis of the reflection effect. The ventromedial prefrontal cortex (vmPFC) is believed to play a critical role in mediating value-based decision-making. In this study, we administered a behavioral test of the reflection effect to three groups of subjects: neurosurgical patients with focal bilateral vmPFC lesions, neurosurgical patients with lesions outside vmPFC, and neurologically healthy adults. Subjects made a series of choices between a sure amount (e.g., gain of $50) and a gamble (e.g., 50% chance of gaining $100, 50% chance of gaining $0). Half the trials featured potential gains while the other half featured potential losses. The sure amounts varied across trials. Relative to the two comparison groups, the vmPFC lesion patients exhibited a significantly greater reflection effect; more gambles selected in the loss condition and fewer gambles selected in the gain condition. This finding demonstrates a critical role for vmPFC in governing susceptibility to bias in decision-making.