Background Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Studies into irAE mechanisms are needed to make a transition from expert-opinion to evidence-based irAE treatment strategies. Methods We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients developing irAEs and remaining irAE-free. PBMCs were immunophenotyped and functionally assessed with multicolor flow cytometry at baseline, after ±3 weeks and ±6 weeks or upon clinically relevant irAEs. Additionally, serum cytokine concentrations for 23 analytes were measured by multiplex immunoassay at the same timepoints. Results We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1 and anti-CTLA-4; cICI), of whom 22 developed clinically relevant irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly effector memory T cells, as well as Th17-associated and possibly antibody-mediated immune responses. The latter response was reflected in cICI toxicity by rising CXCL13 and IL-21 levels, but without changes in CD21lo, memory, class-switched or newly activated B cell subsets. Anti-PD-1 monotherapy-inflicted irAEs were associated with a modestly enhanced Th1-associated response compared to irAE-free patients, only reflected by increasing serum CXCL9 and CXCL10, but without cellular changes in Th1/Tc1 subsets. PD-1+LAG-3+double-positive (DP) CD8+T cells retained their proinflammatory potential in all treatment groups, regardless of irAE development. Especially DP CD8+T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. In all patients with irAEs, highly cytotoxic CD57+CD8+T cells were abundant. Conclusions Peripheral blood immune responses are substantially different between cICI and anti-PD-1 monotherapy-treated patients. ICI-induced toxicity is clearly dominated by an enhanced Th1-associated response, but in cICI we also found evidence for Th17-associated and possibly antibody-mediated responses. CD4+effector memory T cells were the principal cycling cells in irAEs after cICI. Together, our data add to the growing body of evidence that irAEs may be antibody-mediated and driven by newly activated CD4+helper T cells, specifically after cICI.