In vitro activity of rifampicin has been shown against H. pylori. It has also been reported that the prevalence of H. pylori is low in patients with tuberculosis treated with rifampicin. Clinical trials are required to establish the efficacy of rifampicin as a salvage therapy for eradication of H. pylori. We aimed to evaluate the efficacy of rifampicin-based salvage therapy for eradication of H. pylori in patients with peptic ulcer disease. Twenty-eight patients with peptic ulcer disease who either had failed eradication of H. pylori or had a recurrence of H. pylori following successful eradication were included in the prospective study. The inclusion criteria included one or more failed attempts at eradication and presence of H. pylori infection as evidenced by positivity of at least two of three tests: rapid urease test (RUT), 14C urea breath test (UBT), and histology. The subjects were treated with a 10-day regimen consisting of rifampicin, 450 mg od, tetracycline, 1 g bd, and esomeprazole, 40 mg bd. Four weeks after completion of therapy, H. pylori status was assessed by RUT, 14C, UBT, and histology. Liver function tests were done before and at the end of therapy. The study subjects included 25 males and 3 females with a mean age of 33.7+/-8.92 years (range: 22-65 years). The median duration of symptoms was 42 months, with a range of 1-180 months. The median number of eradication attempts was two, with one prior attempt in 6 (21.4%), two attempts in 19 (67.9%), and three attempts in 3 (10.7%) patients. Successful H. pylori eradication as defined by concomitant negativity of RUT, UBT, and histology with special stains was achieved in 32.1% (9/28) of patients by intention-to-treat and 33.3% (9/27) of patients by per-protocol analysis. This pilot study suggests that rifampicin-based regimes have no role as salvage eradication therapy in refractory cases of H. pylori infection with peptic ulcer disease.