Background: The aims of the present multicenter pilot study were to examine the feasibility and usability of two different smartphone-based monitoring systems (the Pulso system and the Trilogis-Monsenso system) from two IT companies in patients with bipolar disorder, developed and selected to be testes as a part of a European Union funded Pre-Commercial Procurement (the NYMPHA-MD project). Methods: Patients with bipolar disorder (ICD-10), > 18 years of age during a remitted, partial remitted or mild to moderate depressive state (HDRS-17 < 25) from Italy, Spain and Denmark were included. Patients were randomized 1:1 to the use of one of two smartphone-based monitoring systems. The randomization was stratified according to study location (Italy, Spain, Denmark) and all patients were followed for a 4 weeks study period. Usability and feasibility were evaluated using the Computer System Usability Questionnaire, and the Usefulness, Satisfaction, and Ease of use Questionnaire. Results: A total of 60 patients aged 18–69 years with bipolar disorder (ICD-10) recruited from Italy, Spain, Denmark were included—59 patients completed the study. In Denmark, the patients evaluated the Trilogis-Monsenso system with a statistically significant higher usability compared with the Pulso system. In Italy and Spain, the patients evaluated no statistically significant difference between the two systems in any of the categories, except for the usefulness category favoring the Trilogis-Monsenso system (z = 2.68, p < 0.01). Conclusions: Both monitoring systems showed acceptable usability and feasibility. There were differences in patient-based evaluations of the two monitoring systems related to the country of the study. Studies investigating the usability and feasibility during longer follow-up periods could perhaps reveal different findings. Future randomized controlled trials investigating the possible positive and negative effects of smartphone-based monitoring systems are needed.