Purpose: Patients receiving prolonged acute mechanical ventilation (PAMV), although comprising a third of all mechanical ventilation (MV) patients, consume two-thirds of all the resources allocated to MV, and their numbers are projected to double by 2020. By virtue of their prolonged hospital length of stay (median LOS, 17 days), they are subject to such nosocomial infections as Clostridium difficile-associated disease (CDAD), the incidence and age-adjusted case fatality rate of which doubled between 2000 and 2005. We examined the rates and outcomes of CDAD among adult PAMV patients. Methods: We analyzed 2005 data from the Health Care Utilization Project/Nationwide Inpatient Sample from the Agency for Healthcare Research and Quality. PAMV and CDAD were identified using the International Classification of Diseases, ninth revision, clinical modification codes 96.72 and 008.45, respectively. Results: Among 64,910 adult PAMV patients who were discharged in 2005, 3,468 patients (5.34%) had a concurrent diagnosis of CDAD (PAMV patients who were discharged with concomitant diagnosis of CDAD [CDAD+]). CDAD+ patients who were discharged were older (mean [± SD] age, 66.7 ± 15.9 vs 63.7 ± 16.9 years, respectively; p < 0.001) and were more likely to have been admitted to the hospital from a long-term care facility (5.7% vs 2.9%, respectively; p < 0.001) than PAMV patients who were discharged without CDAD (CDAD-). Although crude hospital mortality rates did not differ among PAMV patients who were discharged from the hospital by CDAD status (CDAD+, 32.6%; CDAD-, 33.0%; p = 0.598), both unadjusted calculations and propensity-score adjustment showed a substantial increase in LOS (6.1 days; 95% confidence interval [CI], 4.9 to 7.4) and total costs ($10,355; 95% CI, $7,540 to $13,170) among CDAD+ patients. Conclusions: PAMV patients have an order of magnitude higher risk of having CDAD than other hospitalized patients. Concurrent CDAD infection is associated with increased hospital LOS and costs. The PAMV population is an attractive target for aggressive measures aimed at CDAD prevention.