Background: Typhoid fever is a global health problem. The World Health Organization (WHO) estimates that the current annual global burden of typhoid is approximately 22 million new cases, 5% of which are fatal. Methodology: To assess the trends in antibiotic resistance in 100 Salmonella enterica serovar Typhi strains were isolated from the blood of patients in Nairobi, Kenya, from 2004 to 2006. All isolates were tested against ampicilin, chloramphenic, nalidixic acid, ciprofloxacin, cotrimoxazole, cefuroxime, cefriaxone, amoxycillin/clavulanic acid, tetracycline and gentamycin. Susceptibility and resistance were determined using MIC and disk diffusion tests. Results: From 2004 to 2006 a total of 100 strains were studied; 70% of the isolates were multidrug resistant (MDR) while 15% of the isolates were sensitive to all drugs tested. Of 13 isolates that were resistant to ciprofloxacin and nalidixic acid by disk diffusion, 11 had an MIC of 0. 25 µg/ml while two isolates had an MIC of 1.00 µg,/ml. Resistance in ampicillin decreased from  88% in 2004 to 64% in 2005; this increased to 76% in 2006. Similar trends were observed for four other antibiotics tested. Conclusion: The prescription of first-line antibiotics used in the treatment of S. Typhi should be stopped temporarily. Drugs such as cipfloxacin would be useful in the treatment of typhoid caused by MDR S. Typhi. There is need to monitor the resistance in flouroquinolones as resistance to these drugs has been observed and they are the current drugs used to treat typhoid.