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AIM The aim of this study was to explore which peri-implant crevicular fluid (PICF) protein pattern is associated with the active peri-implantitis process. MATERIALS AND METHODS Peri-implant crevicular fluid from 25 peri-implantitis sites were subjected to proteomic analysis using liquid chromatography-tandem mass spectrometry before and at 3, 6 and 12 months after treatment, to identify associations between PICF protein pattern and implant loss, bleeding on probing, pocket depth and enamel matrix derivative (EMD) treatment. RESULTS Clustering of subjects based on their 3-12 months PICF proteomic profiles by principal component analysis defined two major clusters. Cluster 2 differentiated from cluster 3 by 52 proteins (R2  = 90%, Q2  = 80%) and belonging to cluster 2 was associated with implant loss (p = 0.009) and bleeding on probing (p = 0.001). Cluster 3 was associated with implant survival and EMD treatment (p = 0.044). CONCLUSION Here, we demonstrate that a specific PICF proteomic profile associates with active peri-implantitis process and implant loss.