The chronic effects of dietary caffeine, theophylline, and theobromine on urinary calcium excretion were investigated in the adult male rat. The effect of acutely administered adenosine and adenosine analogues on methylxanthine-induced hypercalciuria was concurrently investigated. When rats were fed equimolar amounts of theobromine, caffeine, and theophylline, it was found that urinary calcium excretion increased; on day 7 values were increased over controls (p less than 0.05) by 54, 146, and 208%, respectively. On day 20, an injection of adenosine reduced calcium excretion in methylxanthine-treated rats to levels not different from control values. In another series of experiments, theophylline was fed to a group of rats to establish hypercalciuria. Three adenosine analogues N6-(L-2-phenylisopropyl)adenosine (R-PIA), N6-(D-2-phenylisopropyl)adenosine (S-PIA), and 5'-(N-ethylcarboxamido)adenosine (NECA) with different adenosine receptor specificities (A2,A1, and weakly A2, respectively) were administered to different groups of theophylline-fed and control rats, and their calcium excretions were measured. It was found that the order of efficacy of the analogues in reducing calcium excretion was NECA greater than R-PIA greater than S-PIA, which is consistent with the receptor being A2. A proportion of the methylxanthine-induced hypercalciuria may be due to adenosine antagonism.