Objectives: The aim of the present study was to compare the periodontal and the microbiological changes in patients treated with Invisalign® thermoplastic orthodontic appliances (Align Technology, Santa Clara, California) over 2 months of treatment. Study Design: 2 groups of consecutive patients were examined during treatment in the period between March 2016 and May 2016. Patients and Methods: The periodontal status of 19 patients (7 males,12 females; 10 in the Invisalign® group and 9 in the control group) was clinically assessed applying API, BOP, and PD indices. All patients were part of the clientele of the dental practise of Dr. Waltraud Frotz in Vienna. In addition, saliva samples were taken at 5 different appointments and microbiologically tested for 11 key periodontal pathogens. The molecular genetic detection of the microorganisms was carried out via real-time PCR using the micro-IDent plus 11 ver. 1.0 test (Hain Lifescience, Nehren, Germany). Results: The tests for the 11 pathogens were positive for both groups at an average of 67% (relative standard deviation 44%) at the beginning and during the study. Both groups showed comparably high initial values. The assessment of the last sample showed a general tendency towards reduction of the microbial load which was more pronounced within the Invisalign® group. The initial scores for the periodontal indices were comparable. During the course of the treatment API remained unchanged while BOP, PD as well as the propensity to periodontal inflammation rose within the Invisalign® group. Conclusion: In spite of the Invisalign®-treatment requiring full coverage of the teeth and partial coverage of the keratinized gingiva for at least 20 hours per day, the present study showed no tendency towards an increase of periodontal pathogens. In fact, both groups showed a general reduction in the number of the analyzed species with differences between the individual samples of T0 and T5 only being significant for Fusobacterium Nucleatum (both groups) and Eikenella Corrodens (control group). The general reduction is likely due to an improved oral hygiene at home. The slight deterioration of the scores for the periodontal indices of the Invisalign® group might be of a transitory nature which remains to be examined in the continuation of this study.