We report the results of two nationwide surveillance studies of Clostridium difficile infection conducted during 2008 and 2009 in Sweden. The first study aimed to identify and quantify the proportion of C. difficile isolates with decreased susceptibility to moxifloxacin, particularly those of PCR-ribotype 027. From December 2007 to September 2008, 20 of 28 regional laboratories sent 585 isolates to the Swedish Institute for Infectious Disease Control for typing. A majority of the isolates (454 of 585; 78%) belonged to four PCR ribotypes (012, SE37, 017 and 046), all clustered in geographical regions. Only two type 027 isolates were found, both from the same patient. In the second study, involving all 28 regional laboratories, all consecutive C. difficile isolates collected during two time periods in 2009 (n=364) were typed and tested for susceptibility to clindamycin, erythromycin, moxifloxacin, metronidazole and vancomycin. The three most common PCR ribotypes were SE21, 001 and 020 (22% of all isolates). Types 012, 017, and 046 were geographically clustered and associated with decreased susceptibility to moxifloxacin, clindamycin and erythromcin. The extent of moxifloxacin prescription was highly variable among counties, indicating a need for careful monitoring of prescription rates to follow its role in C. difficile epidemiology.