This study examined changes in biomarkers of exposure (BoE) after five days of nicotine-salt pod system (NSPS) use, compared to continuation of usual cigarette smoking and cigarette abstinence, among adult combustible cigarette smokers.A randomized, open‑label, parallel‑cohort, confinement study of healthy adult smokers, naive to NSPS use was conducted. Participants (N=90) were randomized to 6 cohorts (n=15 each): exclusive ad libitum use of NSPS (4 flavors: Virginia Tobacco, Mint, Mango, Creme), continuation of usual brand cigarette smoking, or cigarette abstinence. Total nicotine equivalents and biomarkers of exposure (NNN, NNAL, 3-HPMA, MHBMA, S-PMA, HMPMA, CEMA, 1-OHP, and COHb) were measured.Eight non-nicotine BoEs, measured in urine, were reduced by an aggregate of 85.0% in the pooled NSPS cohort; increased by 14.4% in the cigarette cohort (P<0.001 for pooled NSPS vs. cigarette); and reduced by 85.3% in the abstinence cohort (P>0.05; 99.6% relative reduction between pooled NSPS vs. abstinence). Similar changes in individual BoEs were also observed (P<0.001 for each BoE between pooled NSPS vs. cigarettes; and abstinence vs. pooled NSPS; P>0.05 for each BoE between pooled NSPS vs. abstinence). Blood COHb decreased by 71.8% in the pooled NSPS cohort and 69.1% in the abstinence cohort (P>0.05) and increased by 13.3% in the cigarette cohort (P<0.001). Mean total urine nicotine equivalents increased in the pooled NSPS and cigarette cohorts by 9% and 26%, respectively, and did not significantly differ (P>0.05).Complete switching from cigarettes to NSPS produced significant reductions in key non-nicotine BoEs associated with cigarette smoking.