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PrEP users might be more exposed to other sexually transmitted infections (STIs) and toxicities. Our aim was to evaluate the trend of STIs and toxicities in an Italian PrEP cohort. A retrospective multicentre cohort study (Modena, Genova and Padova) including TDF\/FTC-PrEP users followed from Jan-2019 to Jul-2022. Data collection included demographics, toxicities and STIs detection: <jats:italic>N.gonorrhoeae<\/jats:italic> (NG), <jats:italic>C.trachomatis<\/jats:italic> (CT), <jats:italic>M.genitalium<\/jats:italic> (MG), <jats:italic>T.vaginalis<\/jats:italic> (TV), <jats:italic>T.pallidum<\/jats:italic> (TP), HAV, HBV and HCV. Two-hundred-forty-four persons included: 97% males; median age 39 years (IQR 33\u201347). A nearly incremental trend was recorded in NG and MG incidences, especially after 2020: from 5.7% to 2.3% in 2020, to 10.3% and 6.5% in 2021 and to 9.6% and 4.8% in the first 7 months of 2022. CT and TP presented a variable trend, while only two TV diagnoses were done. The test for trend for ordered groups across years showed no statistical significance for all the STIs and the annual proportions of subjects with multiple STIs varied. At logistic regression, only history of STIs was associated to risk of new STIs. Twenty cases of nephrotoxicity were recorded, leading to PrEP interruption in 1 case only. Concluding, STIs incidence and nephrotoxicity in our cohort were consistent with other data from literature. In 2020 we observed a lower STIs incidence, probably as consequence of COVID-19 restrictions. An incremental trend could be hypothesized regarding NG, MG and CT incidence. 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