Purpose: The aim of this split-mouth study was to evaluate the behaviour of soft and hard tissue around implants with two different surface treatments. Materials and methods: 10 patients (5 men, 5 women) were treated with fixed partial dentures supported by implants. Each patient received at least 2 implants (1 control, 1 test) into an edentulous quadrant. The control implants (Osseotite, OSS) had a dual acid-etched (DAE) surface in the apical portion and a machined coronal part; test implants (Full Osseotite, FOSS) had a completely DAE surface. Machined healing abutments were placed on control implants and DAE abutments on test ones. After 3 months from surgery, a mini-invasive sample of soft tissue was collected from the first 7 patients recruited for the study (4 women and 3 men). The samples were analysed by microRNA (miRNA) microarray. Standardised periapical radiographs were taken to investigate interproximal bone levels at baseline (immediately after implant insertion), 2 months, 6 months, and 1 year post-implant placement. Plaque index (PI), bleeding on probing (BOP) and periodontal depth (PD) were recorded at 3 and 6 weeks, and at 2, 3, 6 and 12 months post-implant placement. Differences in bone resorption over time were evaluated with the Friedman test followed by post-hoc Wilcoxon signed ranks tests. Differences in bone resorption, PI, BOP and PD between the two types of implant over time were assessed by the repeated measures ANOVA test for ranked data. A p ≤0.05 was considered statistically significant. Statistical analyses were carried out with SPSS v.20. Microarray data were processed by GeneSpring® software and their overall variability was examined by box-plot analysis, scatter-plot analysis, hierarchical cluster analysis (HC) and principal component analysis (PCA). Individual miRNAs modulated by the experimental treatments were identified by volcano-plot (thresholds 2-fold and P0.05), support vector machine and k-nearest neighbour analyses. The results of miRNA microarray were compared with measured clinical parameters. Results: Control implants showed greater bone resorption compared to test ones; however, the difference was not statistically significant. Greater plaque accumulation was found for test surfaces, but the difference was not statistically significant. No statistically significant differences in BOP and PD were found. miRNA microarray analysis led to the following findings: - Implant sites with low plaque accumulation and absence of BOP had a gene expression profile similar to those with plaque deposits and an absence of BOP; sites with both high PI and high BOP had a completely different profile. - Implant sites with BOP present presented similar gene expression profiles independently from the type of implant surface. - Implant sites with high PI and normal bone resorption had a different expression profile from the other experimental conditions. - Implant sites with normal bone resorption despite high BOP differed from the other experimental conditions. This gene expression profile resembled that of FOSS implants. - Implant surface affected bone resorption: groups having similar bone resorption characteristics (normal vs. increased) clustered differently according to the implant type. Conclusions: DAE surfaces showed more plaque accumulation than machined ones; however, this did not affect the health of soft peri-implant tissue. In fact, BOP values did not differ between test and control implants. Furthermore, DAE surfaces induced lower bone resorption compared with machined ones. miRNA analysis suggested that soft tissue inflammation is more related to a specific host characteristic (gene expression profile) rather than to the presence of plaque or to a given implant surface. Some specific miRNA profile might be able to protect implant sites from bleeding and bone resorption irrespective of plaque accumulation. Possible future applications of the present findings include the use of the identified biomarkers for diagnosis and as drugs or coatings for implant surfaces in order to improve the health of peri-implant tissues. Keywords: dental implants, peri-implant tissue, microRNA, titanium surfaces