Background: Novel nicotine delivery systems, delivering nicotine without smoke, are complementary to tobacco harm reduction strategy. We present the first data from the clinical assessment of a novel nicotine-containing product, similar in appearance to a cigarette, that generates an inhalable aerosol from nicotine powder when air is drawn through it without the help of electronics. Methods: This was an open-label, randomized, crossover study to evaluate the nicotine pharmacokinetic (PK) profiles of four product variants, differing in nicotine content (1 or 2 mg), nicotine-powder particle size, and presence/absence of mentholated flavor, following a fixed puffing regimen and a one-hour ad libitum use period. A compartmental PK analysis approach was used to perform nicotine baseline correction. Safety and product satisfaction were assessed to provide further insights on product acceptance and product use. Eighteen healthy adult smokers were randomized in this study conducted in Switzerland and registered at www.clinicaltrials.gov (NCT03369340). Results: The mean of maximal nicotine concentrations (Cmax) ranged between 1.1 and 3.1 ng/mL for the different product variants during fixed regimen and were reached after 15–22.5 minutes. During each ad libitum session, subjects used between one and four products to reach maximal nicotine concentrations (Cpeak) between 2.6 and 5.4 ng/mL. Lowest extent of nicotine exposure was observed for the 1 mg variant, while the presence/absence of flavor and nicotine powder particle size did not influence the PK parameters for both regimens. Product satisfaction, assessed using an adapted version of the modified cigarette evaluation questionnaire, was similar across variants, with slightly lower scores for the unflavored variant, and was also similar to previously reported scores for cigarettes. Product variants were well tolerated, as indicated by the adverse events collection, safety monitoring, and cough assessment. Conclusions: This novel nicotine-containing product shows potential as an alternative to cigarettes for smokers in terms of product satisfaction and simplicity of use without the involvement of electronics.