Antibiotic resistance in Africa is increasing but insufficiently recognized as a public health problem. However, there are scarce data for antimicrobial resistance trends among bloodstream isolates in sub-Saharan Africa. Antimicrobial drug resistance trends among bacteria isolated from blood of children < 15 years of age admitted to the Manhiça District Hospital in Mozambique during May 2001-April 2006 were monitored by disk diffusion. We documented a linear trend of increasing resistance throughout the study period to chloramphenicol among isolates of Non-typhi Salmonella (P < 0.001), Escherichia coli (P = 0.002), Staphylococcus aureus (P < 0.001), and Haemophilus influenzae (P < 0.001). Increasing resistance to ampicillin was also observed for H. influenzae isolates (P < 0.001). We report trends of increasing resistance among the most frequent etiologies of bacteremia to the most commonly used antibiotics for empirical therapy in this community. Quinolones and third-generation cephalosporines may be needed in the short term to manage community-acquired infections. Copyright © 2010 by The American Society of Tropical Medicine and Hygiene.