The Cognitive Bias Task (CBT) is a multiple-choice response selection paradigm characterized by inherent ambiguity. All items offer a range from extremely context-dependent to extremely context-invariant responses. Lateralized prefrontal lesions produce extreme, and opposite, response biases on CBT in right-handed males. Healthy control subjects perform in the middle range. Findings suggest a dynamic balance between two synergistic decision-making systems in the frontal lobes: context-dependent in the left hemisphere and context-invariant in the right. The robust lateralized effects, which are dependent on task ambiguity, are sensitive and specific to frontal dysfunction. CBT is discussed in comparison with the Wisconsin Card Sorting Test as a potential cognitive activation task for functional neuroimaging of the frontal lobes.