Hepatitis C virus (HCV) infection is a serious global health problem and a cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Bioinformatics software has been an effective tool to study the HCV genome as well as core domains. Our research was based on employing several bioinformatics software applications to find important mutations in domain 1 of core protein in Iranian HCV infected samples from 2006 to 2017, and an investigation of general properties, B-cell and T-cell epitopes, modification sites, and structure of domain 1. Domain 1 sequences of 188 HCV samples isolated from 2006 to 2017, Iran, were retrieved from NCBI gene bank. Using several tools, all sequences were analyzed for determination of mutations, physicochemical analysis, B-cell epitopes prediction, T-cell and CTL epitopes prediction, post modification, secondary and tertiary structure prediction. Our analysis determined several mutations in some special positions (70, 90, 91, and 110) that are associated with HCC and hepatocarcinogenesis, efficacy of triple therapy and sustained virological response, and interaction between core and CCR6. Several B-cell, T-cell, and CTL epitopes were recognized. Secondary and tertiary structures were mapped fordomain1 and core proteins. Our study, as a first report, offered inclusive data about frequent mutation in HCV-core gene domain 1 in Iranian sequences that can provide helpful analysis on structure and function of domain 1 of the core gene.