Needlestick and sharps injuries expose healthcare workers to bloodborne pathogens, primarily hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The risk of transmission per percutaneous exposure varies dramatically: HBV is the most infectious at 6-30% risk (depending on HBeAg status of source), HCV at 0.5-1.8%, and HIV at 0.3% for percutaneous and 0.09% for mucous membrane exposure. Factors that increase transmission risk include deep injury, visible blood on the device, device used for arterial or venous access, hollow-bore needle (vs. solid/suture needle), and high viral load in the source patient. The mechanism of viral transmission involves inoculation of infected blood through disrupted skin (needlestick, cut) or contact with mucous membranes (splash to eyes, nose, mouth). HIV targets CD4+ T lymphocytes and macrophages via the gp120-CD4 receptor interaction, establishing infection within 72 hours—the window for post-exposure prophylaxis (PEP) to interrupt viral integration into host DNA. HBV vaccination provides >95% protection with adequate anti-HBs titer (≥10 mIU/mL), making it the most preventable bloodborne occupational infection.