Background: P4M3 is an e-cigarette developed as an alternative product for smokers with the potential to reduce the risk of smoking-related diseases. This study investigated the nicotine pharmacokinetic (PK) and pharmacodynamic (PD) effects of four P4M3 variants compared with subjects’ own e-cigarette. Methods: This was a single-center, open-label, concentration-ranging study to evaluate the nicotine PK profile and PD effects (puffing topography, craving and sensory assessment, product evaluation) in healthy adult users of e-cigarettes and using P4M3 (1.7%, 3%, or 4% e-liquid nicotine concentration) or their own e-cigarette (mean e-liquid nicotine concentration 3%). Subjects used all products with a fixed puffing regimen (12 puffs) and ad libitum for 60 minutes. Fifteen subjects were randomized to one of two sequences to cross-over the use of P4M3-1.7% variants. The study was registered at www.clinicaltrials.gov (NCT03379740). Results: Following the fixed puffing regimen, there was a nicotine concentration-dependent increase in mean maximum nicotine concentrations (Cmax) for P4M3 variants from 5.1 to 12.0 ng/ml, while mean Cmax for subjects’ own e-cigarette was 5.4 ng/ml. Median time to Cmax was 7–10 minutes for all products. Nicotine exposure, assessed as area under the curve over four hours (AUC0- 4h), for P4M3 variants increased for higher nicotine concentrations from 7.0 to 13.6 h×ng/mL, while mean AUC0-4h for subjects’ own e-cigarette was 7.8 ng/ml. Craving reduction and mean puff volume were comparable for all products. Following ad libitum use, there was a nicotine concentration-dependent increase in mean AUC0-4h for P4M3 variants from 28.6 to 52.8 h×ng/mL, while mean AUC0-4h for subjects’ own e-cigarette was 33.8 h×ng/mL. Product evaluation subscale scores were higher for subjects’ own e-cigarette. Mean total puff volume was 2050 mL for subject’s own e-cigarette and 1930 mL for P4M3-4% but higher for other P4M3 variants, ranging from 2600–2950 mL. Conclusions: Nicotine exposure increased with increasing nicotine concentrations of P4M3 variants and was comparable to or exceeding subject’s own e-cigarette. There were no safety signals observed.