Multidrug resistance in cancer is significantly limits the effectiveness of cancer chemotherapy. The main purpose of the present study is to investigate the role of autophagy induced by glucose starvation in apoptosis induction in multidrug resistant human leukemia HL60/ADR cell line. The present data indicates that glucose starvation induced autophagy as determined by the level of LC3 protein (autophagy marker), whereas serum deprivation did not induce autophagy at the same time points. The induction of autophagy by glucose starvation exerted a great effect on apoptosis induction and enhancement. It was found that glucose starvation induced caspase3 cleavage more intensive than serum deprivation. Also, glucose starvation up-regulated the      pro-apoptotic BAX and down-regulated the anti-apoptotic BCL-1 proteins representation, but serum deprivation did not affect both protein levels. The lipid mediator, Ceramide was the most candidate key player in autophagy and/or apoptosis induction after glucose starvation. Accordingly, Ceramide level was determined by DGK assay, ceramide level was elevated after glucose starvation and decreased after serum deprivation. Elevation of Ceramide by glucose starvation was found to be due to down-regulation of sphingomyelin synthase and glucosyl ceramide synthase activities and up-regulation of neutral sphingomyelinase activity. The opposite case of these enzyme activities was obtained in serum deprived cells. The current data throw the light on autophagy induced by glucose starvation as a powerful tool for apoptosis induction in multidrug resistance malignancy. Abbreviations: SM; sphingomyelin, Cer; Ceramide, DG; Diethyl Glycerol, SMS; Sphingomyelin Synthase, GCS; Glucosyl ceramide Synthase, GCer; Glucosyl Ceramide, ASMase; Acid Sphingomyelinase, NSMase; Neutral Sphingomyelinase, Glu; Glucose, Ser; Serum, MDR; Multidrug Resistance.