Purpose Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand F-18-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. Methods PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (V-T) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. Results In controls, V-T was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean V-T corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. Conclusion Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.