Results of numerous human imaging studies and nonhuman neurophysiological studies on "reward" highlight a role for frontal, striatal, and thalamic regions in operant learning. By integrating operant and functional neuroimaging methodologies, the present investigation examined brain activation to two types of discriminative stimuli correlated with different contingencies. Prior to neuroimaging, 10 adult human subjects completed operant discrimination training in which money was delivered following button pressing (press-money contingency) in the presence of one set of discriminative stimuli, and termination of trials followed not responding (no response-next trial contingency) in the presence of a second set of discriminative stimuli. After operant training, subjects were instructed to memorize a third set of control stimuli unassociated with contingencies. Several hours after training, functional magnetic resonance imaging was performed while subjects viewed discriminative and control stimuli that were presented individually for 1,500 ms per trial, with stimulus presentations occurring, on average, every 6 s. Activation was found in frontal and striatal brain regions to both sets of discriminative stimuli relative to control stimuli. In addition, exploratory analyses highlighted activation differences between discriminative stimuli. The results demonstrate the utility of coupling operant and imaging technologies for investigating the neural substrates of operant learning in humans. (Contains 6 figures and 1 table.)