Aims/hypothesis. To determine the independent and potentially synergistic effects of agonists for PPARγ and RXR on glucose and lipid metabolism, as well as gene expression, in human skeletal muscle cell cultures. Methods. Fully differentiated myotubes from non-diabetic subjects and subjects with Type II (non-insulin-dependent) diabetes mellitus were chronically (2 days) treated with LG100 268 (4 μmol/l), an RXR agonist, or troglitazone (4.6 μmol/l), a PPARγ agonist or both, to determine the effects on glucose uptake, activity of glycogen synthase and palmitate oxidation. Results. The combination of both agents increased glucose uptake (60 ± 9 % compared to control subjects) but not either agent alone (16 ± 9 and 26 ± 6 % for LG100 268 and troglitazone, p < 0.01, respectively). The agent LG100 268 alone had little effect on the activity of glycogen synthase but the effect of troglitazone increased with LG100 268 (p < 0.05). With chronic exposure, LG100 268 upregulated palmitate oxidation (53 ± 12 % increase, p < 0.005), in a way similar to troglitazone (68 ± 23 %, p < 0.005). Synergism was observed when both agonists were combined (146 ± 38 %, p < 0.005 vs either agent alone). Treatment with either agent led to about a twofold increase in the expression of fatty acid transporter (FAT/CD36). Troglitazone upregulated PPARγ protein expression, whereas LG100 268 had no effect. Furthermore, neither LG100 268 nor troglitazone had any effect on the protein expression of RXR isoforms or PPARα. Conclusion/interpretation. Co-activation of PPARγ and RXR results in additive or synergistic effects on glucose and lipid metabolism in skeletal muscle, but unlike troglitazone, LG100 268 does not alter expression of its own receptor. [Diabetologia (2001) 44: 444–452]