Mmap to the rescue! 
use strict;
use warnings;
use Mmap;
open my $file, '<', 'big21gfilename.ext' or die;
mmap my $f, 0, PROT_READ, MAP_SHARED, $file or die;
my $re = '('+join('|',@ARGV)+')';
$re = qr($re);
printf "%d: %s\n", pos($f), $1 while $f =~ /$re/g;

[download]

unless, of course, your file has lines, in which case 

use strict;
use warnings;
my $re = '('+join('|',@ARGV)+')';
$re = qr($re);
open my $file, '<', 'big21gfilename.ext' or die;
while( <$file> ) {
  printf "%d (%d): %s\n", $., pos, $1 while /$re/g
}

[download]
will probably be faster.
[]s, HTH, Massa

In reply to Re: Fastest Search method for strings in large file by massa
in thread Fastest Search method for strings in large file by Anonymous Monk

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