Thiazolidinediones cause sodium retention and oedema by a direct effect on the kidneys. The aim of this study was to use the technique of head-out water immersion to investigate the effects of rosiglitazone on sodium and volume homeostasis in subjects with type 2 diabetes mellitus. The volume expansion response to water immersion was compared to the response on a non-immersion control day, in 12 non-diabetic male subjects and 8 diet controlled type 2 male diabetic subjects with hourly blood and urine sampling over a 4 hour period. This was repeated after both groups had taken rosiglitazone 4mg daily for 7 days. Immersion produced a natriuresis in both groups (p<0.001). An impairment of this natriuresis was seen in the diabetic subjects (p=0.006). However when taking rosiglitazone, there was no significant difference in immersion-induced natriuresis compared to non-diabetic controls (p=0.2). There was an immersion-induced rise in atrial natriuretic peptide (ANP) and urinary cyclic guanosine monophosphate (cGMP), in the healthy subjects (ANP p=0.001, cGMP p=0.043), which was not seen in the diabetic subjects (ANP p=0.51, cGMP p=0.74). Rosiglitazone restored the immersion-induced increase in cGMP excretion and rise of ANP in the diabetic group (ANP p=0.048, cGMP p=0.009). This study confirms that type 2 diabetic subjects have an impaired natriuretic response to acute volume expansion, which appears to be enhanced rather than diminished by rosiglitazone. This may be related to its effects in increasing natriuretic peptides and restoring the impaired cGMP excretion to volume expansion.