To conduct a prospective controlled study assessing the safety and efficacy of the additional administration of subcutaneous low-dose heparin in patients receiving oral pentosan polysulfate (PPS) medication for interstitial cystitis. A total of 41 patients with interstitial cystitis who reported efficacy of oral PPS medication were divided into three groups (major, intermediate, and minor PPS response), according to their therapeutic response to PPS. Patients received 3 × 5000 IU/day heparin for 2 days, followed by 2 × 5000 IU/day for 12 days. The maintenance dose was 5000 IU/day heparin. We used 17 patients randomly taking PPS alone as the control group. The primary endpoint was a change in overall well-being. Secondary endpoints were changes in pain, urgency, frequency, functional bladder capacity, and the O’Leary-Sant index. Overall, 10 patients were identified as responders at 3 months (24.4%) and 9 patients at 6 months (21.9%) compared with no responders in the control group (P ≤0.001). At 3 months, 7 (31.8%) of 22 patients in the minor response group reported a statistically significant overall improvement in their well-being compared with 1 (12.5%, P ≤0.001) of 8 patients of the intermediate group and 2 (18.2%, P ≤0.001) of 11 patients of the major response group. A significant amelioration of pain intensity was observed in the minor response group at 3 and 6 months. The concurrent administration of low-dose heparin and oral PPS appears to be a safe and efficacious treatment modality. The subcutaneous administration of heparin appeared to be predominantly of value for patients with interstitial cystitis and an initial minor response to PPS.