Hepatocellular carcinoma (HCC) is the second leading cause of cancer death in many regions of Asia and the etiology of human HCC is clearly multi-factorial. The development of effective markers for the detection of HCC could have an impact on cancer mortality and significant health implications worldwide. The subjects presented here were recruited based on the serum alpha-fetoprotein level, which is an effective marker for HCC. Further, the chromosomal alterations were elucidated using trypsin G-banding. HCCs with p53 mutations have high malignant potential and are used as an indicator for the biological behavior of recurrent HCCs. The functional polymorphism in the XRCC1 gene, which participates in the base-excision repair of oxidative DNA damage, was associated with increased risk of early onset HCC. Thus, in this investigation, the p53 and XRCC1 gene polymorphisms using the standard protocols were also assessed to find out whether these genes may be associated with HCC susceptibility. Blood samples from HCC patients (n = 93) were collected from oncology clinics in South India. Control subjects (n = 93) who had no history of tumors were selected and they were matched to cases on sex, age, and race. Peripheral blood was analyzed for chromosomal aberrations (CAs) and micronuclei (MN) formation. p53 and XRCC1 genotypes were detected using a PCR–RFLP technique. Specific biomarkers on cytogenetic endpoints might help in diagnosis and treatment measures. The frequencies of genotypes between groups were calculated by χ2 test. A statistically significant (p < 0.05) increase in CA was observed in HCC patients compared to their controls as confirmed by ANOVA and MN shows insignificant results. The study on p53 Arg72Pro and XRCC1 Arg399Gln polymorphism in HCC patients demonstrated differences in allele frequencies compared to their controls. The present study indicates that chromosomal alterations and the genetic variations of p53 and XRCC1 may contribute to inter-individual susceptibility to HCC. A very limited role of genetic polymorphism was investigated in modulating the HCC risk, but the combined effect of these variants may interact to increase the risk of HCC in the South Indian population.