The objective of this study was to explore whether the percentage of inappropriate empirical antibiotic treatment in patients with bacteremia changed over time and to understand the factors that brought on the change. Three prospective cohorts of patients with bacteremia in three different periods (January 1st, 1988 to December 31st, 1989; May 1st, 2004 to November 30, 2004; May 1st, 2010 to April 30, 2011) were compared. Analysis was performed on a total of 811 patients. In 2010-2011, 55.9% (76/136) of patients with bacteremia received inappropriate empirical treatment, compared with 34.5% (170/493) and 33.5% (55/164) in the first and second periods, respectively, in a significant upward trend (p = 0.001). Resistance to antibiotics increased significantly during the study period. The following variables were included in the multivariate analysis assessing risk factors for inappropriate empirical treatment: study period (third period) [odds ratio, OR = 2.766 (95% confidence interval, CI, 1.655-4.625)], gender (male) [OR = 1.511 (1.014-2.253)], pathogen carrying extended-spectrum beta-lactamases [OR = 10.426 (4.688-23.187)], multidrug-resistant Acinetobacter baumannii [OR = 5.428 (2.181-13.513)], and skin/soft infections [OR = 3.23 (1.148-9.084)]. A model excluding microbiological data included: gender (male) [OR = 1.648 (1.216-2.234)], study period (third period) [OR = 2.446 (1.653-3.620)], hospital-acquired infection [OR = 1.551 (1.060-2.270)], previous use of antibiotics [OR = 1.815 (1.247-2.642)], bedridden patient [OR = 2.019 (1.114-3.658)], and diabetes mellitus [OR = 1.620 (1.154-2.274)]. We have observed a worrisome increase in the rate of inappropriate empirical treatment of bacteremia. We need tools that will allow us better prediction of the pathogen and its susceptibilities during the first hours of managing a patient suspected of a severe bacterial infection.