The effects of pH buffering on the pain of administration and efficacy of three local anesthetics (1% lidocaine, 1% lidocaine with 1:100,000 epinephrine, and 1% mepivacaine) were investigated in a randomized, prospective, double-blind study of 25 adult volunteers. Plain and buffered solutions of the three local anesthetics were prepared, and a 0.5 intradermal injection of each was administered. Pain of anesthetic infiltration was rated from zero to ten. The area of anesthetized skin surrounding each injection site was measured at time intervals following each injection. Buffering the local anesthetics significantly reduced the mean quantitative pain estimates compared to the nonbuffered controls: 1) 1% lidocaine compared with buffered 1% lidocaine, 4.9 +/- 0.4 versus 1.1 +/- 0.2 (P less than 10(-6)); 2) 1% lidocaine with epinephrine compared with buffered 1% lidocaine with epinephrine, 5.1 +/- 0.4 versus 1.8 +/- 0.4 (P less than 10(-6)); and 3) 1% mepivacaine compared with buffered 1% mepivacaine, 5.1 +/- 0.4 versus 0.9 +/- 0.2 (P less than 10(-6)). Onset, extent, and duration of skin anesthesia were not statistically altered by pH buffering. The pain of local anesthetic administration can be dramatically reduced by buffering the local anesthetic prior to its infiltration. Anesthetic efficacy is not compromised, and patient acceptance may be significantly increased.