PubMed, EMBASE and conference abstracts were reviewed systematically to determine the clinical and economic burden associated with Clostridium difficile infection (CDI) acquired and treated in European healthcare facilities. Inclusion criteria were: published in the English language between 2000 and 2010, and study population of at least 20 patients with documented CDI acquired/treated in European healthcare facilities. Data collection was completed by three unblinded reviewers using the Cochrane Handbook and PRISMA statement. The primary outcomes were mortality, recurrence, length of hospital stay (LOS) and cost related to CDI. In total, 1138 primary articles and conference abstracts were identified, and this was narrowed to 39 and 30 studies, respectively. Data were available from 14 countries, with 47% of studies from UK institutions. CDI mortality at 30 days ranged from 2% (France) to 42% (UK). Mortality rates more than doubled from 1999 to 2004, and continued to rise until 2007 when reductions were noted in the UK. Recurrent CDI varied from 1% (France) to 36% (Ireland); however, recurrence definitions varied between studies. Median LOS ranged from eight days (Belgium) to 27 days (UK). The incremental cost of CDI was £4577 in Ireland and £8843 in Germany, after standardization to 2010 prices. Country-specific estimates, weighted by sample size, ranged from 2.8% to 29.8% for 30-day mortality and from 16 to 37 days for LOS. CDI burden in Europe was most commonly described using 30-day mortality, recurrence, LOS and cost data. The continued spread of CDI and resultant healthcare burden underscores the need for judicious use of antibiotics.