Background: Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use. Objective: To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort. Methods: We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed. Results: Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7–2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106–124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160–188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04–1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18–2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00–0.99/1000 PYFU). Conclusion: During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs.