Background: 1-nitropyrene (1-NPy) is one of the most abundant nitro-polycyclic aromatic hydrocarbons particularly in diesel exhausts. It is a mutagenic and carcinogenic pollutant very widespread in the environment. So the discovery of antimutagenic agents is essential. Harpagophytum procumbens (HP) is traditionally used as anti-inflammatory and analgesic particularly against painful osteoarthritis. Harpagoside (HS), its major iridoid glycoside, is considered as the main active component. Objective: The aim of the present study was to evaluate the antimutagenic activity of HS and HP extracts against mutagenic activity of 1-NPy. Materials and Methods: The antimutagenic activity was investigated using the in vitro cytokinesis-block micronucleus assay in cultured human lymphocytes. Cells were exposed to HS or HP extracts before (pretreatment), during (co-treatment), and after (posttreatment) treatment with 1-NPy. Results: Results showed that HS significantly reduced the mutagenicity of 1-NPy in pretreatment and particularly in co-treatment, whereas all HP extracts significantly reduced the genotoxicity in the three protocols. Conclusion: These results suggested that HS was strongly involved in antimutagenic activity of HP extracts in co-treatment, but other components in HP extracts participated in this activity in pre- and post-treatment.