Little is known about the etiology of myelodysplastic syndromes (MDS). A hospital-based case-control study of 354 adult de novo MDS cases and 452 controls was conducted to investigate associations between lifestyle characteristics and MDS risk. The distribution by French-American-British (FAB) type was 67 (19%) refractory anemia (RA), 38 (11%) refractory anemia with ringed sideroblasts (RARS), 43 (12%) chronic myelomonocytic leukemia (CMML), 136 (38%) RA with excess blasts (RAEB), and 70 (20%) RAEB in transformation (RAEBT). Multivariate logistic regression analyses were performed among all MDS cases and among each FAB type and gender. For all MDS combined, family history of hematopoietic cancer (odds ratio (OR) = 1.92), smoking (OR = 1.65), and exposure to agricultural chemicals (OR = 4.55) or solvents (OR = 2.05) were associated with MDS risk. Among RA/RARS cases, smoking (OR = 2.23) and agricultural chemical exposure (OR = 5.68) were the only risk factors identified. For RAEB/RAEBT cases, family history of hematopoietic cancer (OR = 2.10), smoking (OR = 1.52), and exposure to agricultural chemicals (OR = 3.79) or solvents (OR = 2.71) were independent risk factors. Drinking wine reduced risk for all FAB types by almost 50% (OR = 0.54). We found a joint effect between smoking and chemical exposure with the highest risk among smokers exposed to solvents/agricultural chemicals (OR = 3.22). Results from this large study suggest that several factors play a role in MDS predisposition with possible joint effects. Risk profiles seem to differ by FAB type and gender.