Chronic inflammation marked by elevated interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptor (sTNFR)-1, and sTNFR-2 levels may play a detrimental role in aging and HIV infection. This study aimed to evaluate the relationships of circulating IL-6 with sTNFR-1 and sTNFR-2 levels in an aging cohort of injection drug users (IDUs) with or at high risk for HIV infection. The AIDS Linked to the Intravenous Experience (ALIVE) study is a community-recruited, prospective observational study of former and current IDUs in Baltimore, Maryland. Serum IL-6, sTNFR-1, and sTNFR-2 levels were measured using standard ELISA. Multivariate linear regression analysis was employed, adjusting for age, sex, HIV status, injection drug use, comorbidities, as well as HIV viral load, CD4 T cell counts, and antiretroviral therapy where appropriate. The analysis included 1,178 participants (316 HIV positive and 862 HIV negative). In the adjusted model, sTNFR-1 and sTNFR-2 were individually associated with IL-6 (regression coefficient: 0.877 and 0.556, respectively, for all participants; 0.607 and 0.407 for HIV positives; and 0.999 and 0.628 for HIV negatives, all p < 0.0001). In the model combining sTNFR-1 and sTNFR-2, the associations for sTNFR-1 remained significant (0.693 for all participants, p < 0.0001; 0.417 for HIV positives, p < 0.05; and 0.840 for HIV negatives), while those for sTNFR-2 were no longer significant. sTNFR-1 and sTNFR-2 were positively associated with IL-6 in ALIVE participants. These findings provide initial insight into the in vivo relationship between TNF-α activation and IL-6 and a basis for further investigations into potential mechanisms underlying chronic inflammation in aging and HIV infection.