BACKGROUND AND PURPOSE Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Delta(9)-tetrahydrocannabinol have been extensively investigated, the bioactivity of Delta(9)-tetahydrocannabinol acid (Delta(9)-THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Delta(9)-THCA through modulation of PPAR gamma pathways. EXPERIMENTAL APPROACH The effects of six phytocannabinoids on PPAR gamma binding and transcriptional activity were investigated. The effect of Delta(9)-THCA on mitochondrial biogenesis and PPAR gamma coactivator 1-alpha expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdh(Q111/Q111) cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Delta(9)-THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NPA). KEY RESULTS Cannabinoid acids bind and activate PPAR gamma with higher potency than their decarboxylated products. Delta(9)-THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdh(Q111/Q111) cells and by mutHtt-q94 in N2a cells. Delta(9)-THCA, through a PPAR gamma-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Delta(9)-THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. CONCLUSIONS AND IMPLICATIONS Delta(9)-THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.