Immunohistochemical staining with non-specific IgG reliably labels a subset of neurons in both rat and human brain, overlapping the distribution of cortico-limbic D2 receptors (D2R). We used haloperidol to up-regulate rat D2R to observe any associated changes in IgG immunostaining. Rats were treated with haloperidol or vehicle for 30 d. Some rats were assessed for D2R up-regulation with apomorphine. The remaining rats were processed immunohistochemically and IgG-stained cells counted and statistically analysed in three cortico-limbic areas. Other brain regions were surveyed qualitatively. Positive (anti-glial fibrillary acidic protein or anti-tyrosine hydroxylase staining) and negative (antisera omitted) controls were performed on adjacent sections. Haloperidol dramatically the IgG staining areas quantified with all surveyed regions significantly decreased. Positive control staining was robust, ruling out generalized immunoreactivity reduction. These observations raise the possibility of an immunological effect of haloperidol in the brain. The identification and function of these IgG-labelled sites may have useful implications for psychosis.