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In addition to fever, rash, and arthralgia/arthritis, myalgia is another dominant symptom in Chikungunya virus (CHIKV) infection. How CHIKV induces myalgia is unclear. To better understand the viral factors involved in CHIKV-induced myalgia, CHIKVs were isolated from patients with and without myalgia designated myalgia-CHIKV and mild-CHIKV, respectively. The response of myoblasts to infection by the two groups of clinical isolates of CHIKV was investigated. Both groups of CHIKV replicated well in primary human myoblasts. However, the myalgia-CHIKVs replicated to a higher titer and caused the death of infected myoblast more rapidly than the mild-CHIKVs. CHIKV-infected myoblasts increased production of four out of five inflammatory cytokines examined (MCP-1, IP-10, MIP-1α, and IL-8) in comparison to mock-infected cells. Comparison between the myoblast inflammatory cytokine responses showed that myalgia-CHIKVs were stronger activators of cytokines than mild-CHIKVs. This means that recent epidemic strains of CHIKV exhibited different degrees of myoblast permissiveness as evidenced by differences in the ability to replicate and to stimulate inflammatory responses in myoblasts. This data suggest that the myopathic syndrome in recent epidemics is dependent upon the strain of CHIKV. J. Med. Virol. 87:733–739, 2015. © 2015 Wiley Periodicals, Inc.