Injections are among the major procedures in health care facilities which need to be handled under sterile conditions. Unsafe injections have been found to cause deaths due to its associated complications.  The burden of injection site infections is unknown in Tanzania. This study was designed to determine the burden of injection site infections and factors associated to it among underfives in a district hospital, northern Tanzania. This cross-sectional hospital-based study was conducted at Huruma Hospital in Rombo District, northern Tanzania from November to December 2013. This study included children of less than five years attending reproductive child health clinic for the routine immunization. Demographic data and clinical information were collected using pre-tested self-administered questionnaires, with both closed and open ended questions. A total of 200 underfives attending clinics for vaccination were recruited. Majority (n=125, 62.5%) were males. Out of 200 underfives, 60 (30%) were infants. Injection site infections were observed in 18 (9%, 95% CI: 5-12.9) of children; of whom 13 (72.2%) were females. Factors associated with injection site infections were female sex (OR 5.03, 95% CI; 1.58-18.71, P=0.001), severe malnutrition (OR 90, 95% CI; 9.5-398, p<0.001) and HIV infection (OR 21.5, 95% CI; 4.27-114.19, p<0.001). In conclusion, injection site infection rate is relatively high in this hospital and was associated with female sex, malnutrition and positive HIV status.  Proper care and follow up should be instituted when injections are given to this high risk group of underfives.