PDZ protein interacting specifically with Tc10 or PIST is a mammalian trans-Golgi resident protein that regulates subcellular sorting of plasma membrane receptors. PIST has recently been found to play an important role in regulating viral pathogenesis. Alteration in PIST expression is linked to the reprogramming of cell surface receptors which is crucial in determining herpes simplex virus1 infection. In this context, PIST is crucial in triggering autophagy via Beclin 1 -PI3KC3 pathway. However, there is complete lack in our knowledge on the role of this protein in any parasitic infection. Leishmania parasites infect their host macrophage cells via phagocytosis and their survival within the parasitophorous compartment has recently been found to be dependent on host autophagy by a yet to be identified mechanism. Using Leishmania major (L. major)- macrophage infection model system we, for the first-time report here that in infected macrophages Golgi resident PIST protein migrates towards the parasite containing compartment. We have also found that PIST associates with Beclin 1, however, not with LC3 within the L. major parasite containing compartment of infected macrophages. Further, we performed genetic ablation of PIST by siRNA and observed that knockdown of macrophage PIST in turn helps in parasite replication. Contrary to this, overexpression of PIST in macrophages restricted the multiplication of L. major. Collectively, our study for the first time reveals that PIST is essential in regulating intracellular parasite, L. major infection within macrophage cells.