Introduction. Clostridium difficile-associated disease (CDAD) has been, clearly associated with the use of broad-spectrum antibiotics worldwide. However, information about CDAD is scarce in Mexico and Latin America. Material and methods. We studied clinical characteristics, associated factors and outcomes of all cases of CDAD diagnosed by toxin A fecal detection in a tertiary care hospital in Mexico City from 2003 to 2007. Cases were paired with controls by date of hospital discharge. Results. A total of 3170 tests were performed; we evaluated 113 cases and 226 controls, with an incidence of 5.04 cases x 1000 hospital discharges during the study period. There was no difference in gender or primary diagnosis. After multivariate analysis, we found as significant risks the following: use of H2 blockers (OR 21.73, 95% CZ 7.14-66.67, p < 0.001), age < 65 y (OR 10.21, IC95% 2.74-38.00, p < 0.001), prior hospitalization within 12 weeks of diagnosis (OR 4.39, IC95% 1.81-40.64, p < 0.001), prior use of cephalosporins (OR 3.41, CI 95% 1.56-7.46, p = 0.002), and fluoroquinolones (OR 3.11, IC95% 1.12-8.62, p = 0.029), stay at the intensive care unit (ICU) (OR 2.76, IC95% 1.38-5.49, p = 0.004); and, extended hospital stay (OR 1.10, IC95% 1.05-1.16, p < 0.001) or antimicrobial use before diagnosis (OR 1.05, IC95% 1.01-1.09, p = 0.010). We described an outbreak of 12 cases occurred in August of 2005 (29.5 cases per 1,000 discharges). We also observed a higher seasonal incidence of disease during the summer in the study period. Conclusions. The use of H2 blockers, age < 65 years, prior hospitalization or earlier use of cephalosporins or fluoroquinolones, as well us stay at the ICU were independent risk factor for CDAD.