The methods which require endoscopy for the examination of the gastric mucosa are called invasive (direct) methods. Several tests can be performed on the gastric mucosa obtained by endoscopy: Rapid urease test, histology, smear (cytology), culture and polymerase chain reaction. A combination of at least two tests with high sensitivity and specificity is recommended for clinical trials, and, when possible, for clinical management of patients. In clinical practice the invasive methods should be carried out only in those patients to be treated with eradication regimes. All invasive methods rely on gastric biopsy samples. Therefore, the specimens should be taken under optimal conditions. Several factors guide the site and the number of biopsy specimens for identification of Helicobacter pylori infection. In pre-treatment diagnosis, the biopsies should be taken from the distal antrum (2 cm from the pylorus). The number required depends on the diagnostic method used: in Helicobacter pylori eradicated patients the same number of biopsies for histology and culture should be taken from the antrum and corpus. The sensitivity and specificity of the Rapid urease test varies from 80-90% the results are known very quickly and the cost is very low. The maximal accuracy of histology is obtained with: an optimal specimen processing, an adequate staining and an experienced observer. This method of biopsy processing facilitates the identification of Helicobacter pylori which is commonly located on the superficial and foveolar epithelium. Sensitivity depends on the observer's experience and the extent of biopsy sampling. In general, the histological method has a sensitivity and specificity of 90-95%. In patients treated by proton pump inhibitors, antibiotics or bismuth salts two-four weeks prior to biopsy, the bacteria may be restricted to the corpus or fundus. Culture is strictly indicated in patients after failure of two or more eradication regimens to test for susceptibility and resistence. Specificity is 100% and sensitivity depends on the experience and interest of the microbiologist. The indication of polymerase chain reaction is only for research, specially, in molecular epidemiology and for fingerprinting.