Globally, hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma and liver cirrhosis. For clinical decision making, genetic variation in the interferon-λ (IFNL) cluster has been utilised as a baseline predictor of natural and interferon-based treatment-induced viral clearance. In Vietnam, where HCV genotypes 1 (g1) and g6 predominate, no prior studies have been conducted investigating associations of IFNL3/4 polymorphisms with spontaneous clearance (SC) or HCV viral load (VL) in chronic infection. In this study, we have investigated the host genetic variations in IFNL loci to determine the association of IFNL3/4 polymorphisms with HCV SC and baseline VLs in a Vietnamese HCV-seropositive cohort. The majority of the cohort harboured major homozygous polymorphisms in IFNL3/4 cluster (i.e. rs12979860-CC: 82.7%; rs8099917-TT: 84.8% and rs368234815-TT/TT: 85.5%) and the SC rates in these groups were 15.8%, 16.3% and 15.7%, respectively. In the minor allele groups, the resolution rates were lower (12% in rs12979860 non-CC, 9.1% in rs8099917 non-TT and 9.5% in rs368234815 non-TT/TT). Furthermore, in individuals harbouring minor alleles, females achieved higher SC rates than males. HCV g6-infected rs12979860 major homozygous individuals had significantly higher viral loads than individuals with minor alleles (CC: 6.56 log IU/ml vs. non-CC: 5.66 log IU/ml; P = 0.021). The association between IFNL3/4 genotypes with elevated HCV VL observed in HCV g6-infected individuals may have implications for the progression of liver disease in Southeast Asian countries where this viral genotype predominates and therefore warrants further studies.