BACKGROUND: Bloodstream infections (BSIs) caused by Candida glabrata have increased substantially. Candida glabrata is often associated with resistance to fluconazole therapy. However, to our knowledge, risk factors for fluconazole-resistant C glabrata BSIs have not been studied. METHODS: A case-case-control study was conducted at 3 hospitals from January 1, 2003, to May 31, 2007. The 2 case groups included patients with fluconazole-resistant C glabrata BSIs (minimum inhibitory concentration > or =16 microg/mL) and patients with fluconazole-susceptible C glabrata BSIs (minimum inhibitory concentration < or =8 microg/mL). Hospitalized patients without C glabrata BSIs were randomly selected for inclusion in the control group and were frequency matched to cases on the basis of time at risk. Two case-control studies were performed using this shared control group. The primary risk factor of interest, previous fluconazole use, was evaluated at multivariate analyses, adjusting for demographic data, comorbid conditions, and antimicrobial exposures. RESULTS: We included 76 patients with fluconazole-resistant C glabrata BSIs, 68 patients with fluconazole-susceptible C glabrata BSIs, and 512 control patients. Previous fluconazole use (adjusted odds ratio [95% confidence interval], 2.3 [1.3-4.2]) and linezolid use (4.6 [2.2-9.3]) were independent risk factors for fluconazole-resistant C glabrata BSIs; previous cefepime use (2.2 [1.2-3.9]) and metronidazole use (2.0 [1.1-3.5]) were independent risk factors for fluconazole-susceptible C glabrata BSIs. CONCLUSIONS: Previous fluconazole use is a significant risk factor for health care-associated fluconazole-resistant C glabrata BSIs. Future studies will be needed to evaluate the effect of decreasing fluconazole use on rates of fluconazole-resistant C glabrata BSIs.