Background: Tacrolimus (FK) and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause acute nephrotoxicity. The expanding use of tacrolimus and the intense consumption of NSAIDS increase the chances of their simultaneous use. Methods: Rats receiving a nonselective COX inhibitor (diclofenac, D) and FK or a selective COX-2 inhibitor (rofecoxib, RO) and FK were treated with FK (2 mg/kg/day), D (10 mg/kg/day), RO (3 mg/kg/day), FK+D, FK+RO and vehicle for 7 days on low-salt diet. Results: Both associations significantly impaired glomerular filtration rate (GFR; 0.63 ± 0.06 ml/min/100 g in FK+D, 0.83 ± 0.06 ml/min/100 g in FK+RO) which did not occur with single drug therapy (0.98 ± 0.03 ml/min/100 g in D, 1.06 ± 0.04 ml/min/100 g in RO, 0.99 ± 0.05 ml/min/ 100 g in FK) or vehicle (1.10 ± 0.05 ml/min/100 g). GFR decrease was significantly higher with FK+D. GFR impairment occurred without RBF or RVR major changes. Mild tubular vacuolization and dilatation and acute degenerative changes were observed in tubular cells. FK+D animals showed a marked weight loss, not observed in the other groups. FK+NSAIDs association decreased FK blood levels (1.73 ± 0.3 ng/ml in FK+D, 1.8 ± 0.3 ng/ml in FK+RO, 3.2 ± 0.4 ng/ml in FK, p < 0.05). Conclusions: The association of FK and nonselective or COX-2 selective NSAIDs in salt-depleted animals caused a significant GFR impairment and decreased FK blood levels.