Background:Typhoid fever is an endemic disease in many developing countries with significant health implications that could sometimes, turn fatal. The study aimed to investigate the antimicrobial susceptibility of Salmonella typhi ( S. typhi ) isolates from stool samples of patients attending secondary health centres in Benue South geographical zone. Methods: One thousand and twenty-two (1022) stool samples were collected from 583 male and 439 female patients presumptively diagnosed with typhoid fever using Widal test. Isolation of S.typhi was according to standard procedure. The antimicrobial susceptibility of S. typhi isolates was tested against 10 different antibiotics, using the disc diffusion method. Results: A total of 447 (43.7%) S. typhi were isolated.Antibiotic resistance pattern showed that 64% (286/447) of the total isolates were resistant to at least two antibiotic classes. The isolates demonstrated the highest resistance to ciprofloxacin (55.6%; 159/286), and azithromycin (53.8%; 154/286). Resistance was highest to cephalosporin (ceftriaxone and ceftazidime) class of antibiotics  (66.1%; 189/286). Isolates, however, showed susceptibility to the carbapenem (imipenem, 286/286), amphenicol (chloramphenicol, 286/286) and aminoglycoside (gentamicin  278/286). A total of 42.7% (122/286) isolates were resistant to three or more antibiotic classes, with different resistance patterns. Conclusion: These findings reveal multidrug resistance of S. typhi to antibiotics, with a possible positive reversing trend in the susceptibility characteristics of S. typhi tochloramphenicol in the study area, bringing to fore the need for adequate measures to control increasing resistance by this important pathogen and reconsideration for chloramphenicol in S. typhi treatment.