Physicians should try to achieve an optimal cure rate with their initial Helicobacter pylori eradication therapy. Most physicians use the same treatment in all their patients. H pylori infection in patients with peptic ulcer disease (PUD) is more likely to be cured than that in patients with functional dyspepsia (FD). Differences in cure rates of 5% to 15% are usually reported, which is considered to be clinically relevant. A plausible biological explanation for this finding suggests that different strains (virulent [cagA+, vacA type s1] compared with nonvirulent strains [cagA–, vacA type s2]) in PUD and FD induce different changes in the gastric mucosa, and this facilitates or impairs antimicrobial efficacy. Physicians should be aware that most published treatment studies have included only PUD patients. This means that in clinical practice cure rates obtained in patients with FD or perhaps uninvestigated dyspepsia are usually lower than those reported in the literature. This has implications for the choice of treatment. Physicians should consider prolonging the duration of initial Helicobacter eradication therapy from seven to 10 to 14 days in patients without ulcers.