Helicobacter pylori infection is very common in the Spanish population and represents the main cause of chronic gastritis, peptic ulcer, and gastric cancer. The last iteration of Spanish consensus guidelines on H. pylori infection was conducted in 2016. Recent changes in therapeutic schemes along with increasing supporting evidence were key for developing the V Spanish Consensus Conference (May 2021). Fourteen experts performed a systematic review of the scientific evidence and developed a series of recommendations that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. An eradication therapy, when prescribed empirically, is considered acceptable when it reliably achieves, or preferably surpass, 90% cure rates. Currently, only quadruple therapies (with or without bismuth) and generally lasting 14 days, accomplish this goal in first- and second-line therapies. A non-bismuth quadruple concomitant regimen (proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole) or a quadruple bismuth-based combination (proton pump inhibitor, bismuth, tetracycline, and metronidazole), are recommended as first-line regimens. Rescue therapies after eradication failure and management of H. pylori infection in peptic ulcer disease were also reviewed.