Nonterpenoid and diterpenoid phenanthrenequinones (PACs) have been found in the plant kingdom. Some of them occur in plants used in traditional Chinese medicine like Tan-Shen whereas others are constituents of orchids that are popular as ornamental plants. Case reports and our own observations in orchid nurseries suggest that some or even all of these PACs possess a distinct sensitizing potency. Occasional exposure (particularly of botanists) to field-grown orchids, as well as occupational contact with sawdust of PAC-containing tropical timbers, caused allergic contact dermatitis. However, experimental studies in guinea pigs to determine the sensitizing capacity of PACs have not been performed so far. Guinea pigs were sensitizied by a modified Freund's complete adjuvant method with four naturally occurring and 22 synthetic PACs in order to find out which and how many substituents at the carbons of the three rings of the PAC will influence the sensitizing power of the molecule. Subsequently, the lowest unoccupied molecular orbital (LUMO) coefficients were calculated to show whether a correlation exists between chemical reactivity and sensitizing capacity. Sensitizing capacity was found to be strong in two PACs, moderate in eight PACs, and weak in ten PACs. Five PACs were extremely weak in sensitizing capacity, and one PAC was completely negative. Two substituents on the left-hand carbons C-7 and C-8 of ring C were shown to be responsible for a strong sensitizing capacity. One methoxy group alone or three of them, especially when localized at C-5, decreased the sensitizing capacity to moderate. Substitution with a methoxy group at C-3 and/or at C-2 of the quinonoid ring itself (ring A) led to a weak sensitizing capacity. The ortho-quinones 1,2-PAC and 9,10-PAC were also weakly sensitizing. In fact, LUMO coefficient calculations corroborated a good correlation between chemical reactivity and sensitizing capacity. Substitution with methoxy groups at C-7 and/or at C-8 of ring C of 1,4-phenanthrenequinone increases the LUMO coefficients at the 2,3 double bond of ring A and thus facilitates nucleophilic substitution of protein nitrogen or sulfur nucleophiles at this electron-deficient double bond. The four naturally occurring PACs that were investigated--cypripedin, denbinobin, annoquinone-A, and latinone--do not fulfill these criteria and are thus only weak sensitizers. However, as-yet-unstudied phenanthrenequinones occurring in plants or trees and having no substituents at C-2 or C-3 of the quinonoid ring must be considered potentially strong allergens.