There is conflict by evidence as to whether therapy with vancomycin plus an aminoglycoside is more nephrotoxic than therapy with either agent alone. Here we report the results of a prospective, non-randomized, open-label study of the incidence of nephrotoxicity in elderly patients who received vancomycin alone (32 patients) or an aminoglycoside alone (67 patients) or in combination (37 patients). The mean (95% confidence limits) incidence of nephrotoxicity, defined as an increase of > or = 44.2 mumol/L in the serum creatinine, was 19% (5-32%) in patients receiving vancomycin alone, 24% (10-38%) in patients receiving vancomycin plus an aminoglycoside, and 12% (4-20%) in patients receiving an aminoglycoside alone (P > 0.05 for all comparisons). The corresponding absolute increases of the serum creatine were 20.3 +/- 23.0 mumol/L (-24.8 to +65.4 mumol/L), 37.1 +/- 53.0 mumol/L (-67.2 to +140.4 mumol/L), and 22.1 +/- 31.8 mumol/L (-40.7 to +94.6 mumol/L). The absolute increase was significantly greater (P < 0.05) in patients receiving vancomycin plus an aminoglycoside than in patients receiving an aminoglycoside alone. A meta-analysis of seven previously published studies combined with our data revealed that the incidence of nephrotoxicity associated with combination therapy is 13.3 +/- 3.1% (7.3-19.4%) greater than therapy with vancomycin alone (P < 0.01) and 4.3 +/- 1.4% (1.6-7.0%) greater than therapy with an aminoglycoside alone (P < 0.05). The clinical relevance of this finding may be limited in that the mean duration of antimicrobial therapy in three of the studies was greater than 21 days.