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The dorsal striatum forms a central node of the basal ganglia interconnecting the neocortex and thalamus with circuits modulating mood and movement. Striatal projection neurons (SPNs) include relatively intermixed populations expressing D1‐type or D2‐type dopamine receptors (dSPNs and iSPNs) that give rise to the direct (D1) and indirect (D2) output systems of the basal ganglia. Overlaid on this organization is a compartmental organization, in which a labyrinthine system of striosomes made up of sequestered SPNs is embedded within the larger striatal matrix. Striosomal SPNs also include D1‐SPNs and D2‐SPNs, but they can be distinguished from matrix SPNs by many neurochemical markers. In the rodent striatum the key signaling molecule, DARPP‐32, is a exception to these compartmental expression patterns, thought to befit its functions through opposite actions in both D1‐ and D2‐expressing SPNs. We demonstrate here, however, that in the dorsal human striatum, DARPP‐32 is concentrated in the neuropil and SPNs of striosomes, especially in the caudate nucleus and dorsomedial putamen, relative to the matrix neuropil in these regions. The generally DARPP‐32‐poor matrix contains scattered DARPP‐32‐positive cells. DARPP‐32 cell bodies in both compartments proved negative for conventional intraneuronal markers. These findings raise the potential for specialized DARPP‐32 expression in the human striosomal system and in a set of DARPP‐32‐positive neurons in the matrix. If DARPP‐32 immunohistochemical positivity predicts differential functional DARPP‐32 activity, then the distributions demonstrated here could render striosomes and dispersed matrix cells susceptible to differential signaling through cAMP and other signaling systems in health and disease. DARPP‐32 is highly concentrated in cells and neuropil of striosomes in post‐mortem human brain tissue, particularly in the dorsal caudate nucleus. Scattered DARPP‐32‐positive cells are found in the human striatal matrix. Calbindin and DARPP‐32 do not colocalize within every spiny projection neuron in the dorsal human caudate nucleus.

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