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HIV and hepatitis C virus (HCV) infections may increase interleukin-6 (IL-6) and C-reactive protein (CRP). However, relationships between inflammatory biomarkers, chronic viral infections, clinical factors, and behavioral factors remain poorly understood.Using linear regression, we modeled cross-sectional associations between loge IL-6 or loge CRP levels and HCV, HIV, injection drug use, and comorbidity among 1191 injection drug users.Mean age was 47 years, 46.0% reported currently injecting drugs, 59.0% were HCV monoinfected, and 27% were HCV/HIV coinfected. In multivariable models, higher loge IL-6 was associated with HCV monoinfection [β = 0.191, 95% confidence interval (CI): 0.043 to 0.339] and HCV/HIV coinfection (β = 0.394, 95% CI: 0.214 to 0.574). In contrast, HCV monoinfection (β = −0.523, 95% CI: −0.275 to −0.789) and HCV/HIV coinfection (β = −0.554 95% CI: −0.260 to −0.847) were associated with lower CRP. Lower CRP with HCV infection was independent of liver fibrosis severity, synthetic function, or liver injury markers; CRP decreased with higher HCV RNA. Increased injection intensity was associated with higher IL-6 (P = 0.003) and CRP (P < 0.001); increasing comorbidity (P < 0.001) and older age (P = 0.028) were associated with higher IL-6; older age was associated with higher CRP among HCV-uninfected participants (P = 0.021).HIV and HCV infections contribute to chronic inflammation; however, reduced CRP possibly occurs through HCV-mediated mechanisms. Findings highlight potentially modifiable contributors to inflammation.