Background and PurposeThe interaction of arrestins with G‐protein coupled receptors (GPCRs) desensitizes agonist‐dependent receptor responses and often leads to receptor internalization. GPCRs that internalize without arrestin have been classified as “class A” GPCRs whereas “class B” GPCRs co‐internalize with arrestin into endosomes. The interaction of arrestins with GPCRs requires both agonist activation and receptor phosphorylation. Here, we ask the question whether agonists with very slow off‐rates can cause the formation of particularly stable receptor–arrestin complexes.Experimental ApproachThe stability of GPCR–arrestin‐3 complexes at two class A GPCRs, the β2‐adrenoceptor and the μ opioid receptor, was assessed using two different techniques, fluorescence resonance energy transfer (FRET) and fluorescence recovery after photobleaching (FRAP) employing several ligands with very different off‐rates. Arrestin trafficking was determined by confocal microscopy.Key ResultsUpon agonist washout, GPCR–arrestin‐3 complexes showed markedly different dissociation rates in single‐cell FRET experiments. In FRAP experiments, however, all full agonists led to the formation of receptor–arrestin complexes of identical stability whereas the complex between the μ receptor and arrestin‐3 induced by the partial agonist morphine was less stable. Agonists with very slow off‐rates could not mediate the co‐internalization of arrestin‐3 with class A GPCRs into endosomes.Conclusions and ImplicationsAgonist off‐rates do not affect the stability of GPCR–arrestin complexes but phosphorylation patterns do.Our results imply that orthosteric agonists are not able to pharmacologically convert class A into class B GPCRs.