During 1989–2002, we studied the antimicrobial resistance of 3928 blood culture isolates of Salmonella enterica serotype Typhi (S. Typhi) in Dhaka, Bangladesh. Overall 32% (1270) of the strains were multidrug-resistant (MDR, resistant to chloramphenicol, ampicillin and trimethoprim–sulphamethoxazole); first detected in 1990 (rate of 8%), increased in 1994 (44%), declined in 1996 (22%, P<0·01 compared to 1994) and re-emerged in 2001 (36%) and 2002 (42%, P<0·01 compared to 1996). An increased MIC of ciprofloxacin (0·25 μg/ml) indicating decreased susceptibility to ciprofloxacin was detected in 24 (18·2%) out of 132 randomly selected strains during 1990–2002; more frequently in MDR than susceptible strains (46·3% vs. 5·5%, P<0·001), and the proportion of them rose to 47% in 2002 from 8% in 2000 (P<0·01). Ciprofloxacin (5 μg) disk diffusion zone diameters of [les ]24 mm as break-point had 98% sensitivity and 100% specificity when compared with a ciprofloxacin MIC of 0·25 μg/ml as break-point for decreased susceptibility; being a useful and easy screen test. All strains were susceptible to ceftriaxone. The emergence of MDR S. Typhi with decreased ciprofloxacin susceptibility will further complicate the therapy of typhoid fever because of the lack of optimum treatment guidelines.