The purpose of this case-control study was to investigate tobacco smoking as a risk factor for myelodysplastic syndromes, emphasizing karyotypic aberrations as markers for exposure and risk differentiation with respect to morphology. We obtained smoking history by interview of 330 cytogenetically investigated adult myelodysplastic syndrome cases and 337 controls, matched with respect to sex, year of birth, and county of living. Smoking for at least 1 year at some time 20 years or less before diagnosis was associated with an elevated relative risk (RR) for primary myelodysplastic syndromes (odds ratio (OR) 1.8; 95% confidence interval (CI) = 1.2-2.7). The results indicated a relation with intensity and duration of smoking as well as a decrease in risk a few years after cessation of smoking. Smoking was associated with an increased RR for primary myelodysplastic syndromes with chromosome 7 abnormalities (OR 5.0; 95% CI = 1.1-23). Elevated RRs were also seen for refractory anemia (OR 2.5; 95% CI = 1.2-5.6) and for refractory anemia with ringed sideroblasts (OR 3.2; 95% CI = 0.88-12). The findings suggest that smoking is a risk factor for myelodysplastic syndromes.