There is an increase in isolation of extended spectrum beta-lactamase (ESBL) producing isolates from clinical samples worldwide. In developing countries the treatment option of ESBL producing isolates is limited. Recently fourth generation cephalosporins have been introduced for use in Tanzania. This study was done to determine in vitro activity of cefepime against ESBL producing clinical isolates. Disc diffusion testing was performed to 235 ESBL producing isolates; of which 73 (31%) were Escherichia coli and 162 (69%) Klebsiella pneumoniae. The sensitivity rate of E. coli and K pneumoniae to cefepime were 15.1% and 4.3%, respectively (P=0.012); intermediate sensitivity rate was observed in 13.7% for E. coli and 19.8% for K. pneumoniae. The mean zones of inhibition diameter among sensitive isolates were 24.9mm and 20.0mm for E coli and K. pneumonia, respectively (P=0.0085). Cefepime is less active against ESBL producing organisms; hence the use.of this drug should be guided using local resistance profile.