Lead acetate – which results in significant damage to the genetic structure of living organisms – is found in many sources that humans use daily. Histocompatibility complex (MHC) genes in the vertebrate play a critical role in immune responses, and are highly polymorphic. Virgin olive oil (VOO) and curcumin are natural compounds having several healthy features including antigenotoxic activities. The present study aimed for determining the effects of VOO and curcumin (versus ZnCl₂, as an antioxidant agent) on Mhc genetic variation of renal tissues of lead acetate-treated mice by using the microsatellite loci. Thirty male albino Swiss mice (Mus musculus) were randomly allotted into 5 groups (n = 6): group “1", the control group; groups “2–5" that received orally lead acetate (400 mg/kg body weight, by gavage for 15 consecutive days) + either distilled water (orally), or ZnCl₂ (4 mg/kg body weight, intraperitoneally injected), or curcumin (500 mg/kg body weight, orally), or VOO (8 mL/kg body weight, orally) for additional 15 consecutive days, respectively. Comparing to the control group, the 2^nd and the 4^th groups showed high polymorphism value (17%) and (21%), respectively; while the 3^rd and 5^th groups showed low polymorphism value (12%) and (15%), respectively, in Mhc genes. The obtained data illustrated the usefulness of virgin olive oil, as compared with the curcumin, in limiting Mhc genetic variation induced by lead acetate in mice.