Author Summary Invasive non typhoid Salmonella spp. (NTS) are an important cause of bloodstream infection in sub-Saharan Africa and associated with a high mortality. Levels of multidrug resistance have become alarmingly high. Treatment therefore increasingly relies on the oral fluoroquinolones such as ciprofloxacin, with third generation cephalosporins such as cefotaxime as alternatives for parenteral treatment. Azithromycin represents another alternative antimicrobial drug. Worldwide, increased use of these drugs is associated with spread of resistance as well, a phenomenon poorly documented in Central-Africa. In the present study, 233 NTS isolates were collected from blood cultures sampled between 2007 and 2011 in DR Congo, mainly from children ≤2 years of age. Most isolates were recovered during the rainy season. Widespread multidrug resistance was confirmed as well as decreased susceptibility to ciprofloxacin, resistance to azithromycin and resistance to third generation cephalosporins. Our findings demonstrate emergence of antibiotic resistance among NTS in DR Congo and underline the need for increased microbiological surveillance, being a prerequisite for rational antibiotic therapy and the development of standard treatment guidelines.