That study showed the multiple antibiotic resistance of variant biotypes of Helicobacter pylori isolates from felines and sheep in Upper Egypt. A total of one hundred and thirty- five isolates were recovered from (6 stomachs and 46 stool) of 52 felines and (66 gastric and 17 milk) of 83 sheep samples in Hurghada, Luxor, and Sohag provinces. Stool samples of felines and serum samples of sheep were sero-examined using a stool antigen test and latex agglutination test of H. pylori, respectively in total percent 67.3%, and 85.5% for enriching felines and sheep specimens, in sterile tubes of supplemented or un-supplemented 5ml thioglycolate broth with 10 µl hemin within 36 hours under microaerophilic condition at 37^c then will be cultivated onto filled plates from 500 ml blood brain heart agar supplemented with 135 µl urea 40% solution, novobiocin 500 µl, vancomycin 25 µl, and amphotericin B 350 µl for 5 days and differentiated microscopically upon gram negative stain, and biochemically upon positive oxidase, and variable enzymatic activity of urease and nitrate reduction that be confirmed by 16srRNA H. pylori polymerase chain reaction in total percent 8.8%. Four H. pylori isolates in each province were detected by antimicrobial susceptibility test to report the highest multiple antibiotic resistance MAR of H. pylori isolates (1.0) plus (0.643) & (0.857) among wide ratio of urease & nitrate reduction isolates U: N (1:1.8) were recovered from Hurghada. But the equal ratio of U: N isolates included the lowest MAR of H. pylori isolates (0.07) plus (0.5), (0.286), and (0.714) were recovered from Sohag.