Smokers who switch completely to e-cigarettes may reduce their relative risk of tobacco-related disease. Effective nicotine delivery from e-cigarettes is important in consumer acceptance. We assessed whether protonated nicotine and e-cigarette devices delivering greater aerosol mass increase nicotine delivery and product liking. A randomised controlled non-blinded eight-arm crossover study was used to assess plasma nicotine pharmacokinetics and product liking for two e-cigarettes (Vype ePen3 and Vype ePen) with various nicotine e-liquid formulations and a conventional cigarette among 24 healthy dual-users of cigarettes and e-cigarettes. Product use and puff count were also assessed. Results show that nicotine bioavailability was greater for Vype ePen3 with greater aerosol mass delivery than for Vype ePen (Cmax, p = 0.0073; AUC0-120 min, p = 0.0102). Protonated nicotine (18 mg/mL, medium protonation) e-liquid yielded higher nicotine bioavailability than unprotonated nicotine (18 mg/mL) e-liquid (Cmax, p = 0.0001; AUC0-120 min, p = 0.0026). There was no significant difference in Tmax between e-liquids. Nicotine bioavailability did not differ between nicotine benzoate formulation (30 mg/mL nicotine, high protonation) and combustible cigarettes (Cmax, p = 0.79; AUC0-120 min, p = 0.13). Vype ePen3 with protonated nicotine delivers nicotine more efficiently with the potential to increase product liking relative to earlier devices using unprotonated e-liquid.