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OBJECTIVE: This study investigated the neural substrates of implicit sequence learning in subjects with and without small animal phobia, in a follow-up to analogous studies of obsessive-compulsive disorder (OCD). METHOD: Ten subjects with specific phobia and 10 healthy comparison subjects were studied by using a serial reaction time task paradigm and functional magnetic resonance imaging. RESULTS: A main effect of condition (implicit sequence learning versus random sequence) was observed across diagnostic groups in the right striatum, as well as in other regions. In the striatum, the a priori region of interest, there were no significant effects of diagnosis or the interaction of diagnosis and condition. CONCLUSIONS: Brain activation in the striatum of subjects with specific phobia does not significantly differ from that of normal comparison subjects during implicit sequence learning. This suggests different pathophysiological mechanisms for specific phobia in contrast to OCD, in which deficient striatal recruitment has been reproducibly found with this paradigm. This approach offers promise for demonstrating diagnostic specificity across different neuropsychiatric disorders based on the presence or absence of deficient striatal activation.