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BACKGROUND: In prostate cancer, tumour expression of cannabinoid CB₁ receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB₁ receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray. METHODOLOGY/PRINCIPAL FINDINGS: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB₁ receptor immunoreactivity (CB₁IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB₁IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival. CONCLUSIONS/SIGNIFICANCE: The present study provides data that is consistent with the hypothesis that at a high CB₁ receptor expression, the Akt signalling pathway becomes operative.