The lack of defined triggers for human inflammatory joint diseases warrants efforts to identify candidate molecules. For this task, it may be an important lead that nonspecific activation of the immune system can precipitate arthritis in rats. Consequently, arthritis-prone rat strains were used to search for disease-triggering factors among molecules which initially induce innate defence reactions rather than specific immune responses. A variety of immunological adjuvants were investigated by intradermal injection into DA and LEW.1AV1 rats and monitoring of clinical signs for 30 days. Several arthritogenic cell-wall structures from yeast and bacteria were identified, such as beta-glucan, lipopolysaccharide and trehalosedimycolate. The test procedures also revealed arthritogens of chemical origin, such as dioctadecyldiammoniumbromide (DDA = C38H80NBr) and heptadecane (C17H36). Furthermore, it allowed the precise definition of arthritogenic determinants of lipids, since C16H34 induced arthritis, whereas the closely related linear hydrocarbons C16H32, C16H33Br and C15H32 did not. The observed pathogenicity of organic lipids raised the question of whether endogenous lipids can also precipitate arthritis. Indeed, this was true for the cholesterol precursor squalene (C30H50). In conclusion, this article describes the rational use of arthritis-prone rat strains to identify arthritogenic factors of both foreign and self origin. Although structurally unrelated, the pathogenic molecules defined here share the feature of being nonspecific triggers of the immune system. This consolidates a general principle for the induction of adjuvant arthritis which may provide clues to the aetiology of human arthritides, including rheumatoid arthritis.