BACKGROUND: The caterpillar of Premolis semirufa, known as Pararama, is found in the Brazilian Amazon, primarily on rubber trees of the genus Hevea. Pararamosis is an inflammatory disease resulting from accidental contact with the caterpillar's bristles, leading to acute and chronic symptoms. Chronic exposure can cause significant osteoarticular deformities, similar to those seen in osteoarthritis and rheumatoid arthritis, due to cartilage degradation and synovial inflammation. Currently, there are no specific treatments for Pararamosis, and research on the molecular mechanisms of the caterpillar's venom and its role in disease pathogenesis is limited. The chronic changes in Pararamosis are thought to be linked to chondrocyte activation and the NF-κB signaling pathway, influenced by the toxic components in the bristles. Understanding these interactions is crucial for developing preventive measures and therapeutic strategies, especially for rubber tappers at risk in the Amazon region. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated the effects of P. semirufa bristle extracts on human chondrocytes, focusing on the activation mechanism of the NF-κB transcription factor and the expression of osteoarthritis markers. Cell viability tests indicated that the extracts did not significantly affect chondrocyte survival. However, supernatant analysis revealed a time- and dose-dependent increase in IL-6 and IL-8 levels. Additionally, the expression of NF-κB and its inhibitor, IκB, was assessed, showing higher levels of phosphorylated IκB, which induces its proteosomal degradation, compared to the negative control, while native IκB expression was greater in the control group. Furthermore, the gene expression profile of treated chondrocytes demonstrated modulation in matrix metalloproteinases (MMPs), aggrecan (ACAN), collagen type II (COL2A1), interleukins (IL6 and IL8), and complement system molecules. CONCLUSIONS/SIGNIFICANCE: These findings highlight the significant impact of P. semirufa bristle extracts on human chondrocyte activation and the inflammatory processes associated with pararamosis.