The delivery and systemic absorption of nicotine are important for assessing the potential safety and efficacy of novel inhaled nicotine delivery devices. We describe an experimental approach for examining systemic nicotine intake, looking at individual variability, comparing JUUL electronic cigarettes and cigarette smoking, and comparing standardized puffing and ad libitum use. Fourteen cigarette smokers who were infrequent e-cigarette users vaped JUUL or smoked cigarettes, both in a standardized session (ten 3.5 s puffs over 5 min) and in a 4 h ad libitum use session. Plasma nicotine concentrations were measured, and using sex and body weight-based population nicotine clearance predictions, systemic nicotine dose was estimated in each session. The pharmacokinetically (PK)-estimated nicotine dose in the standardized session averaged 0.55 mg (range 0.16-0.82) for JUUL and 1.15 mg (range 0.35-4.56) for cigarette smoking. The PK-estimated dose with ad libitum use averaged 4.1 mg (range 0.4-9.5) for JUUL and 5.0 mg (range 1.5-15) for smoking (average 3.4 cigarettes). Within individual correlations, comparing PK-estimated dose for JUUL use with standardized vs ad libitum session was weak (r = 0.45, NS) but was much stronger for cigarette smoking (r = 0.82, p < 0.001). Data from ad libitum use predicted that consumption of the liquid contained in a JUUL pod would correspond to smoking 15 cigarettes, which is similar to that observed in real world studies. We conclude that standardized vaping sessions do not predict usual nicotine self-administration behavior with ad libitum use. With ad libitum use, nicotine intake is much more similar to vaping and smoking and provides a much better predictor of product delivery in the real world. This approach is recommended for screening of novel inhaled nicotine devices and to aid FDA regulatory decision making.