In the present study, a toxic mechanism of silver nanoparticles (AgNPs) was investigated in the nematode, Caenorhabditis elegans, focusing on the involvement of oxidative stress in reproduction toxicity. Initially, AgNPs were tested as potential oxidative stress inducers, and increased formation of reactive oxygen species (ROS) was observed in AgNP-exposed C. elegans. Subsequently, the potential upstream signaling pathway activated in response to AgNP exposure was investigated, paying special attention to the C. elegans PMK-1 p38 mitogen-activated protein kinase (MAPK). Increased PMK-1 p38 MAPK gene and protein expressions were observed in C. elegans exposed to AgNPs. Expression of the p38-dependent transcription factor genes and glutathione S-transferase (GST) enzyme activity was also investigated in wildtype (N2) and pmk-1 mutant (km25) C. elegans exposed to AgNPs. The results indicated that AgNP exposure led to increased ROS formation, increased expression of PMK-1 p38 MAPK and hypoxia-inducible factor (HIF-1), GST enzyme activity, and decreased reproductive potential in wildtype (N2) C. elegans; whereas in the AgNP-exposed pmk-1 (km25) mutant, ROS formation and HIF-1 and GST activation were not observed, and decreased reproductive potential was rescued. These results suggest that oxidative stress is an important mechanism of AgNP-induced reproduction toxicity in C. elegans, and that PMK-1 p38 MAPK plays an important role in it. The results also suggest that GST and HIF-1 activation by AgNP exposure are PMK-1 p38 MAPK-dependent, and that both play an important role in the PMK-1 p38 MAPK-mediated defense pathway to AgNP exposure in C. elegans.