Although 13 etiological theories, including the most recent Theory of Helicobacter pylori, have been proposed to explain the pathogenesis of peptic ulcers, the seasonal variation of the disease has remained an unsolved mystery for ≥90 years. Additionally, the major characteristics and observations/phenomena of peptic ulcers have never been fully understood. To address these challenges, a recently published Complex Causal Relationship with its accompanying methodologies was applied to analyze the existing data. Peptic ulcers were identified as a psychosomatic disease triggered by psychological stress, where Helicobacter pylori plays a secondary role in only the late phase of ulceration. This etiology addresses all the characteristics, observations/phenomena, controversies, and mysteries of peptic ulcers in a series of 6 articles. This fourth article focuses exclusively on the seasonal variation of peptic ulcers. The seasonal changes on the earth periodically alter multiple environmental/social factors, each of which induces psychological stress in a proportion of individuals and result in a monthly incidence of peptic ulcers. The superposition of the monthly incidences caused by climate, work, and vacation reproduces 3 typical fluctuation curves of the seasonal variation. Further discussion suggests that surrounding psychological stress, multiple environmental and social factors, such as tradition, climate, industry, vacation, and well-being policies, work together to cause the diversity of the seasonal variation. A full understanding of the seasonal variation suggests that peptic ulcers are not an infectious disease caused by Helicobacter pylori, but a psychosocial disease associated with multiple environmental/social factors, further validating the etiology identified by the Complex Causal Relationship.