The number of children dying from sepsis in the world has almost doubled in the past 20 years. This is most likely due to the increased number of patients who suffer sepsis. And this may be partly due to the fact that antimicrobial therapy in most developing countries including Ghana is mainly empirical due to a relative lack of appropriate laboratory facilities for culture and sensitivity of bacteria in several health facilities. This study aimed at determining the clinical effectiveness of empirical treatment for neonatal sepsis by Klebsiella at KATH. Eight hundred and two (802) blood specimens from children (in-patients) of age range 1day old to 2years old were cultured on blood agar and MacConkey agar and the isolates investigated. The isolates were identified to the species level using various biochemical tests. The antibiogram of the Klebsiella isolates were determined and compared with the empirical treatment of the patients in the hospital. Klebsiella species were recovered from 51 clinical samples (Prevalence of Klebsiella neonatal sepsis is 6.4%). Gentamicin was the most prescribed agent for the patients (38.7%), amikacin (10.7%), cefotaxime (9.3%), ceftriaxone (8%), chloramphenicol (5.3%), Cottrimoxazole (5.3%), cefuroxime (4%), Tetracycline (2.6%) and ampicillin (1.3%) for the empirical treatment. Intermediate antibiotic susceptibility pattern was shown by 9.8% of patient’s isolates. Also, 37.3% of patient’s isolates showed resistance to all the antibiotics used in the antibiotic susceptibility test. Antimicrobial susceptibility was shown by 36 of patient’s isolates representing 52.9%. Aminoglycosides and third generation cephalosporins were the most prescribed antibiotics. And although empirical treatment is very relevant, it should be combined with laboratory antibiotic sensitivity testing for effective treatment of Klebsiella neonatal sepsis.