This research carried out comprehension testing on a set of symbol-based safety signs using three diverse groups of participants that included adult workers, college students and persons afflicted with cerebral palsy. Few studies have examined “differently abled” populations with respect to safety signs. Open comprehension testing of a set of 17 symbol-based safety signs was carried out using ISO (International Organization for Standardization) 9186 criteria. The intended message for each safety sign was conveyed via two components, a graphical symbol and a surrounding shape–color background. Results showed that most of the signs were not well understood. In some cases, participants were able to correctly understand the meaning of the symbol, but failed to understand the meaning of the shape–color code or vice versa. In general, the adult workers and college students achieved higher comprehension scores than individuals with cerebral palsy. Despite the lower scores obtained by the cerebral palsy group, the pattern of comprehension levels for the “good” and “bad” signs were similar across the three groups. Other findings included statistically significant associations between comprehension and the individual/experience variables (e.g., age, gender, and have a driver’s license). Issues associated with categorizing participant responses, including the use of criteria for separately evaluating the meaning of the symbols and color–shape codes, are discussed.