This is a surveillance study of the antimicrobial resistance of the S. flexneri group in the context of its serotype diversity. It includes 1422 isolates, which were sent to the National Shigella Reference Centre (NSRC) by hospitals and outpatient clinics in Israel during a 3-year period (2000–2002). The strains were identified and classified according to the prevalence and antigenic structure of their serotypes. All samples were checked for resistance to ampicillin (AMP), trimethoprim–sulphamethoxazole (TMP–SMX), ceftriaxone (CRO), tetracycline (TE), nalidixic acid (NAL), and chloramphenicol (C) by the disk diffusion method of Bauer et al. There were significant differences in their resistance to the individual antimicrobials with resistance to AMP, TE and C being lower among the strains of serotype 6 than among those of serotypes 2a and 1b. The resistant phenotypes were also serotype-specific. The similarities both in individual and in phenotype resistance between the rare and the prevalent serotypes (but not serotype 6) may be attributed to their antigenic relatedness. The serospecificity of the antimicrobial resistance was not affected by external factors such as seasonality and source (hospital or outpatient laboratory) of the isolates, and the age and sex of the patients. The serotype-specific approach can assist in properly assessing the problem of the antimicrobial resistance of the Shigella flexneri group and may prove useful for the empirical therapy of shigellosis. The observed interdependency between resistance and the antigenic specificity and relatedness of the S. flexneri serotypes requires additional investigation.