Purpose: Helicobacter pylori has been strongly associated with dyspepsia and eradication of H. pylori after a non-invasive testing is an integral part of most management guidelines. This study evaluated the benefit of serological testing and treatment of H. pylori in Nigerian patients presenting with uninvestigated dyspepsia.Methods: The study was a randomized double blinded controlled trial. 103 consecutive dyspeptic subjects aged between 18 and 50 years were recruited for H. pylori serology. Seropositive dyspeptic subjects were randomized to receive Lansoprazole with or without antibiotics (Clarithromycin 500mg and Metronidazole 400mg twice daily for 7 days). Seronegative dyspeptic subjects received Lansoprazole without antibiotics. Subjects were followed up at 2, 6, and 10 weeks from enrolment to assess dyspeptic symptoms using Global Overall Symptom Scale (GOSS).Results: Of 103 cases enrolled, 23 were seropositive and 80 were seronegative. 10 (9.7%) seropositive were randomly assigned to receive triple therapy while 13 (12.6%) seropositive were randomly assigned to placebo group. The eighty (77.7%) seronegative were assigned to the placebo group. After two weeks of intervention, the mean GOSS for seropositive cases assigned eradication regimen dropped from 4.90 ± 1.66 at presentation to 1.11 ± 0.33. There after to 1.38 ± 0.52 and 1.14 ± 0.38 at six and ten weeks respectively. The mean GOSS for seropositive cases assigned placebo group dropped from 5.00 ± 1.58 at presentation to 1.39 ± 0.65 by two weeks, this later became 1.60 ± 1.27 and 1.22 ± 0.67 at six weeks and ten weeks respectively. Seronegative cases were all assigned into placebo group, their mean GOSS dropped from 5.21 ± 1.48 at presentation to 1.48 ± 0.77 by two weeks after enrolment and subsequently, to mean scores of 1.53 ± 0.95 and 1.44 ± 0.56 at six weeks and ten weeks respectively. Hence, no significant benefit in treatment outcome when seropositive dyspeptics were treated with triple therapy compared with those treated with proton pump inhibitor only, up to 10 weeks after treatment (p = 0.83).Conclusion: Antibiotic treatment for H. pylori offered no benefit over empirical use of proton pump inhibitor in uninvestigated dyspepsia. Proton pump inhibitor should be considered first in the management of uninvestigated dyspepsia.