ABSTRACT Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes persistent arthritis in approximately 25% of people two years after initial infection. There is currently no standard evidence-based treatment for CHIKV chronic arthritis. The French guidelines suggest the use of methotrexate in the treatment of chronic CHIKV arthritis however there are no randomized placebo-controlled trials of methotrexate to support this recommendation. Our long-term goal is to guide the evidence-based treatment of CHIKV arthritis. The main goal of this proposal is to determine the efficacy and pathologic effects on synovitis of 6 months of methotrexate (n=100) versus placebo (n=100) therapy for chronic CHIKV arthritis in Colombia in a randomized controlled trial. Our central hypothesis is that methotrexate will significantly decrease the chronic CHIKV arthritis disease severity compared to placebo and effect CHIKV-induced synovitis via suppression of leukocyte accumulation in synovial tissue. This hypothesis will be evaluated in 2 specific aims. In Aim 1, we will determine the efficacy of oral methotrexate treatment versus placebo for 6 months in chronic CHIKV arthritis. In Aim 2, we will determine the effect of methotrexate on synovial inflammation by obtaining synovial biopsy samples before and after treatment. Rationale: This work will define the role of methotrexate in the treatment of chronic CHIKV arthritis with the goal of advancing the field towards an evidence-based standard treatment. The potential broader impact of this work is the potential identification of the pathologic mechanism of chronic viral arthritis and a possible therapeutic option.