Background: Dyspepsia is a common gastrointestinal complaint seen in clinical practice. The causes are many and the major ones are gastroduodenitis, esophagitis, peptic ulcer disease (PUD), malignancies, parasitic infestations and functional dyspepsia. The frequency of these causes varies significantly in different countries. The advent of flexible endoscopy has made it possible to visualize the mucosa of the entire GIT but this service is yet to be widely available in Tanzania. H.pylori, a gram negative bacterium is known to be associated with various upper gastrointestinal pathologies and was reported to be ubiquitous in Sub-Saharan Africa but recent studies report its decreasing prevalence world wide. Objectives: To determine the types of upper gastrointestinal lesions, the prevalence of H. pylori infection and study the association between the infection and the mucosal lesions. Methods: Two hundred and eight consecutive adult patients with dyspepsia at KCMC were evaluated prospectively from July to January 2009. A detailed personal interview was conducted to establish the demographic and clinical profile of each patient followed by diagnostic EGD. Rapid urease test (CLOTest®,) was done on antral biopsy to check for presence of H.pylori infection. When necessary, biopsy specimen was preserved in 10% formalin for histological examination. Data analysis; Statistical Package for Social Sciences version 15 was used. Relationship was tested using the chi-square at 5% tolerable errors. Odds of occurrences were tested using odds ratio at 95% confidence interval. The difference was considered significant at p<0.05. Results: Among 208 patients with dyspepsia, 111 (53.4%) were female. Their ages ranged between 13 and 95 years and median age was 48 years. The most frequently reported symptoms were epigastric pain (86.1%) and heart burn (58.2%). The most commonly identified endoscopic findings were gastritis (61.10%), GERD (57%) and PUD (24.1%). Malignancies were identified in 11.0% of study subjects. H.pylori infection was detected in 65% of dyspeptic patients. H.pylori infection was significantly associated with gastritis and duodenal ulcer (p<0.001) but not with GERD (p>0.05). Conclusion and Recommendations: GERD, gastritis and PUD are the leading causes of dyspepsia. H.pylori infection is present in 65% of patients with dyspepsia. Treating all dyspeptic patients for H.pylori without confirmation of the infection would be unwise, will lead to unnecessary treatment of significant number of patients, and possibly be not cost-effective. In view of the high frequency of abnormal findings (especially malignancies), patients with dyspepsia should undergo EGD for initial work up.