Despite efforts to eliminate Visceral Leishmaniasis (VL) in India, it continues to be a public health issue due to the occurrence of relapse post AmBisome treatment. The role of host genetics in susceptibility of VL relapse is not clearly understood. Here we have performed whole exome sequencing (WES) on healthy, VL relapse and non-relapse individuals. Comparing the nonsynonymous single nucleotide variants (SNVs) among the VL group (n = 26) and healthy (n = 12) revealed 6 gene variants viz.: MTTP, ABCA4, CIB4, LRRIO1, NANOG, and GCNT4 with a significant correlation (P < 0.01) with VL susceptibility. Twelve variants viz.: EP300, MRS2, GOLGA8K, SCL37A2, HERC5, STIL, WDR4, MINDY4B, B3GNTL1, SAMD7, ATF7IP2 and OR56B4 correlated with VL relapse (n = 14) susceptibility. EP300, a histone acetyl-transferase, was found mutated in all the 14 relapse cases. The expression levels of CCL-2, CSF-1, IL-10, IL-6, PD-1 and CTLA-4 were found higher in the VL relapse cases and may be responsible for M2 macrophage polarization and T-cell exhaustion. Thus, individuals harbouring EP300 variants may have poor immune response leading to relapse.