Background: Patients with end-stage renal disease (ESRD) suffer from high mortality rates of cardiovascular diseases, conditions closely linked to the magnitude of their chronic low-grade inflammation. As heparins have been suggested to possess anti-inflammatory properties, we set out to investigate the impact of long-term treatment with intraperitoneal heparin on local and systemic inflammation in peritoneal dialysis (PD) patients. Methods: In a double-blinded cross-over study, 21 PD patients with ESRD were randomised to inject either 4,500 anti-Xa IU tinzaparin or placebo (isotonic saline) into their morning dialysis bags every day for two periods of 3 months separated by a 1-month wash-out period. Blood and dialysate samples were analysed for inflammatory markers at the start and end of each treatment period. In dialysate, the appearance rates of the inflammatory markers were calculated to adjust for ultrafiltration variations. Results: Eleven patients completed the trial. Treatment with intraperitoneal tinzaparin was accompanied with a median 25.8% reduction of the plasma C-reactive protein concentration (p = 0.032), a 7.3% reduction of the plasma fibrinogen concentration (p = 0.042) and a 54.5% reduction of the dialysate interleukin 6 appearance rate (p = 0.007) compared with placebo. Conclusion: Long-term treatment with intraperitoneal tinzaparin of ESRD patients on PD reduces local and systemic concentrations of inflammatory markers.