To evaluate risk factors for colonization or infection due to multidrug-resistant Pseudomonas aeruginosa (MDRPa) carrying the bla(SPM) gene (SPM-MRDPa) among hospitalized patients, we undertook a case control study at a 480-bed, tertiary-care university hospital. Two different case definitions were used. In the first definition, a case patient (SPM case patient) was defined as a patient who had at least one isolate of SPM-MDRPa (14 patients). In the second, a case patient (non-SPM case patient) was defined as a patient who had at least one isolate of non-SPM-MDRPa (18 patients). For each case patient, we selected two controls, defined as a patient colonized and/or infected by a non-MDRPa isolate during the same study period and with the closest duration of hospitalization until the isolation of P. aeruginosa as cases. The use of quinolones was the single independent predictor of colonization and/or infection by bla(SPM) MDRPa (odds ratio [OR] = 14.70, 95% confidence interval [95% CI] = 1.70 to 127.34, P = 0.01), whereas the use of cefepime was the single predictor of colonization and/or infection by non-bla(SPM) MDRPa (OR = 8.50, 95% CI = 1.51 to 47.96, P = 0.01). The main risk factor for MDRPa was a history of antibiotics usage. Stratification of risk factor analysis by a precise mechanism of resistance led us to identify a specific antibiotic, a quinolone, as a predictor for SPM-MDRPa.