OBJECTIVE To report our quality improvement efforts to reduce total parenteral nutrition (TPN)-associated bloodstream infections, and the results of those efforts, during the period including the first quarter of 2004 through the third quarter of 2010. METHODS A variant on failure modes and effect analysis and existing guidelines were used to develop and modify interventions. Effectiveness of the interventions was assessed by using a graphical depiction of interrupted time-series data on TPN-associated infections per 1000 TPN-days, aggregated across quarters within intervention periods. RESULTS Although initial interventions yielded limited reductions in infection rates, it was not until the implementation of a multifaceted "maintenance intervention bundle" that rates strongly responded. After this key intervention revision, the TPN-associated infection rate decreased between implementation in the first quarter of 2008 from 26.1 to 4.8 per 1000 TPN-days during the 8 quarters aggregated comprising the first quarter of 2008 through the fourth quarter of 2009. The final addition of an alcohol-swab cap resulted in a reduction of rates to 0 for the first three-quarters of 2010. CONCLUSIONS Our evidence suggests that iterative design/redesign of interventions using failure modes and effect analysis has directly reduced TPN-associated bloodstream infections.