We prospectively examined the efficacy of systemic antibiotics and antibiotic catheter locks for the treatment of tunneled hemodialysis catheter related blood stream infections (CRBSI). Patients with clinical signs of tunnel or metastatic infection were excluded. All patients with suspected CRBSI were treated empirically with systemic antibiotics at the onset of symptoms before final culture and susceptibility results were available. Once the organism was identified, antibiotics treatment was tailored and antibiotic catheter locks were instilled after each dialysis treatment. Clearance of infection was documented by negative surveillance cultures after completion of antibiotic course. Out of 46 episodes of CRBSI; 16 were due to gram positive organisms, 22 were due to gram negative organisms, and 8 were polymicrobial (≥2 organisms) infections. 19 cases required removal of dialysis catheter. Antibiotic lock protocol was successful for eradicating infection in 27 of 46 episodes (59%). The likelihood of a clinical cure was identical in both gram-positive and gram-negative infections (63% and 62% respectively). Antibiotic lock protocol remains an option in the treatment of clinically stable patients with CRBSI; however, success rate of this protocol in eradicating the infection is modest.