For 16 years we prospectively observed 530 adult patients with brucellosis to analyze the characteristics of and risk factors for relapse. Clinical and laboratory findings from 86 relapsed patients were milder during the relapse episode when compared with those for the same patients during the initial disease. Blood cultures were positive for Brucella melitensis in 65% of cases during relapse and in approximately 80% of cases during the initial disease. Risk factors that were identified as being independently associated with relapse (by logistic regression analysis) were "less-effective" antibiotic therapy (OR, 8.3; 95% CI, 4.6-15.1), positive blood cultures during initial disease (OR, 2.7; 95% CI, 1.2-6.2), < or = 10-day duration of the disease before treatment (OR, 1.9; 95% CI, 1.1-3.6), male sex (OR, 1.8; 95% CI, 1.02-3.8) and a platelet count of < or = 150 x 10(3)/mm3 (OR, 1.7; 95% CI, 1.1-2.8). These data show that relapse of brucellosis is sometimes difficult to diagnose and that it can be an insidious disease. In addition to inappropriate antibiotic therapy, other factors, such as those indicating a more aggressive disease and/or a deficient immunologic response, seem to play an important role in the relapse of brucellosis.