Background: Health crisis of Multi-drug resistant gram negative bacilli (MDRGNB), including Enterobacteriaceae, seems overwhelming as its worldwide spread causes clinical failure in the therapeutic care of diseases by these pathogens and results in significant morbidity and mortality. Combination therapy, using two or more drugs, may be the last resort for treatment of these multi-drug resistant (MDR) organisms. Objective: to update the antibiotic policy to improve treatment of MDR Enterobacteriaceae infections and to reduce morbidity and mortality rates due to these infections. Methodology: Out of 219 of Enterobacteriaceae strains isolated from different types of infections in Suez Canal University Hospitals (SCUHs), 48 isolates (21.91%) were proved to be MDR, including resistance to imipenem. In vitro assessment of Imipenem-colistin combination on the MDR-Enterobacteriaceae strains was performed using the checkerboard technique. Results: The combination had a synergistic effect on 63.04% of the isolates and additive effect on 23.9%. Indifferent effect was shown in 10.8%, while antagonism was shown in 2.1% of the strains. At least, four-fold reduction in imipenem MIC was proved in 86.9% of the strains, 30.43% turned to be imipenem sensitive with drop of their MICs from ≥ 4 to ≤ 1μg/ml, 15.21% changed to intermediate resistance with MIC decrease from ≥ 4 to 2 μg/ml. Three of the 5 strains that showed indifference and the only strain which showed antagonism were colistin resistant strains. Conclusion: High rates of synergy, in addition to reversal of imipenem resistance, were reported by colistin - imipenem combination against MDR-Enterobacteriaceae, which may encourage clinical trials of combination therapy in treatment of Hospital acquired infections (HAI) by MDR pathogens.