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We conducted a two-phase study to test the reliability and usability of an all-in-one artificial intelligence-based device (ButterfLife), which allows simultaneous monitoring of five vital signs. The first phase of the study aimed to test the agreement between measurements performed with ButterfLife vs. standard of care (SoC) in 42 hospitalized patients affected by acute respiratory failure. In this setting, the greatest discordance between ButterfLife and SoC was in respiratory rate (mean difference −4.69 bpm). Significantly close correlations were observed for all parameters except diastolic blood pressure and oxygen saturation (Spearman’s Rho −0.18 mmHg; p = 0.33 and 0.20%; p = 0.24, respectively). The second phase of the study was conducted on eight poly-comorbid patients using ButterfLife at home, to evaluate the number of clinical conditions detected, as well as the patients’ compliance and satisfaction. The average proportion of performed tests compared with the scheduled number was 67.4%, and no patients reported difficulties with use. Seven conditions requiring medical attention were identified, with a sensitivity of 100% and specificity of 88.9%. The median patient satisfaction was 9.5/10. In conclusion, ButterfLife proved to be a reliable and easy-to-use device, capable of simultaneously assessing five vital signs in both hospital and home settings.