Two hundred fifteen (23%) of 955 episodes of bacteremia (defined as including fungemia) detected in adult patients during 2 years were of unknown origin. Sixty-six percent of episodes of unknown origin were hospital acquired. The median age of patients with bacteremia of unknown origin was 65 years, and their most common underlying disorders were solid malignancy (28% of patients) and diabetes mellitus (18%). Only three factors were associated with bacteremia of unknown origin (as opposed to episodes with a known source): peripheral venous catheterization, hemodialysis, and plasmapheresis. Gram-negative bacteria were isolated from the blood in 62% of episodes of unknown origin; 10% of episodes were polymicrobial. Staphylococci were isolated from 67% of patients undergoing hemodialysis and from 37% of those with diabetes; Pseudomonas species from 15% of patients with hospital-acquired episodes; and Candida species from 21% of patients with a central venous catheter. Fifteen percent of episodes in cancer patients were polymicrobial. Empirical antibiotic treatment was inappropriate in 49% of episodes of unknown origin and in 35% of episodes with a known source (P < .001). Death rates were 44% and 25% in episodes of unknown and known origin, respectively. An unknown source of bacteremia was independently associated with a fatal outcome.