Chikungunya virus (CHIKV) infection often results in a chronic joint condition known as Post-Chikungunya Chronic Inflammatory Joint Disease (pCHIKV-CIJD). This condition disrupts individuals' daily lives and contributes to increased healthcare expenditure. This study investigated the molecular mechanisms underlying pCHIKV-CIJD development by analyzing RNA transcripts, including small RNAs, of whole blood from CHIKV-infected patients. By comparing patients who evolved to pCHIKV-CIJD with those who did not, we identified molecular signatures associated with chronification in acute and post-acute disease phases. These molecules were primarily associated with an altered immune response regulation. Notably, LIFR, an immune receptor that enhanced IL-6 transcription, was down-regulated in the acute phase of pCHIKV-CIJD patients, while its inhibitor, hsa-miR-98-5p, was up-regulated in these individuals. Other downregulated genes include members of immune mechanisms whose impairment can lead to a reduction in the first line of antiviral response, thereby promoting virus persistence for a longer period in these patients. Additionally, pCHIKV-CIJD patients exhibited reduced transcript levels of MMP8, LFT, and DDIT4, genes already implicated in the pathological process of other types of inflammatory arthritis and seemingly relevant for pCHIKV-CIJD development. Overall, our findings provide insights into the early molecular mechanisms involved in the chronification and highlight potential targets for further investigation.