DNA damage may develop at any dose of ionizing radiation. DNA damage activates pathways that regulate cell growth and division or coordinate its replication and repair. The repair pathways, base excision repair (BER) and single-strand break repair (SSBR), can repair such damages efficiently and maintain genome integrity. Loss of this repair process or alteration of its control will be associated with serious outcomes for cells and individuals. This study aimed to determine the relationship between XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), OGG1 (Ser326Cys), and XRCC3 (Thr241Met) SNPs and DNA damage and to identify high-risk individuals with reduced DNA repair capacity. This case-control study was conducted on 80 subjects; 50 subjects working in Clinical Oncology and Nuclear Medicine Department in Assiut University Hospital along with 30 controls. A total of 1 mL blood samples were collected for Single-Cell Gel Electrophoresis Technique (Comet Assay) for detection of DNA damage in those subjects. A total of 3 mL fresh blood samples were collected and analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)–based technique. DNA damage detected by comet test was significantly high in IR-exposed workers than control. Statistically high significant difference was found in exposed subjects versus control subjects regarding the frequencies of the variant alleles of hOGG1326, XRCC1280 & 399, and XRCC3241. The level of DNA damage was not affected by OGG1326 SNPs when comparing subjects of wild genotype with those of (pooled) variants either in the exposed staff or in the control group while XRCC1280, 399 and XRCC3241 variant alleles had an influence on the studied DNA damage biomarker. Moreover, genotyping distribution pattern was highly variable in relation to gender. The present study indicated a relationship between DNA damage detected by comet test and single nucleotide polymorphisms in genes coding for DNA certain repair enzymes. Individuals occupationally exposed to low doses of ionizing radiation could be at great risk and more susceptible to the increased DNA damage if they have inherited genetic polymorphism.