Background: Initiation of antiretroviral therapy (ART) and subsequent virologic suppression reduces immune activation and systemic inflammation. Methods: We examined longitudinal changes in biomarkers of monocyte activation (sCD14, sCD163), and systemic (IL-6, hsCRP, sTNFR-I and D-dimer) and vascular (Lp-PLA2) inflammation in a subgroup (N = 100 per arm) of participants enrolled in a randomized, placebo-controlled trial comparing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF; TAF) to E/C/F/tenofovir disoproxil fumarate (E/C/F/TDF; TDF) in treatment-naïve adults. Results: For 194 participants (TAF, 98; TDF, 96), baseline levels of biomarkers did not differ by treatment arm; there were no differences in biomarker values between groups at weeks 12, 24, or 48 (p > 0.05), except IL-6 at week 12 (p = 0.012). Among all participants (combining groups), there were statistically significant declines from baseline observed for D-dimer, sCD163, and sTNFR-1 by week 12 and IL-6 by week 24. The proportion of participants with Lp-LA2 levels < 200 ng per mL (p = 0.250) or hsCRP levels <3000 mg per L (p = 0.586) was unchanged through week 48. Conclusions: We observed equivalent declines in biomarkers of monocyte activation and systemic inflammation in treatment-naïve adults treated with TAF or TDF for 48 weeks, suggesting that TAF and TDF have equivalent impact on immune activation and inflammation.