Well..it has been an interesting session.

Thanks again all for the input.

To answer a question posed above:

Yes, as described in the original post, it is a two-column database. The Primary Key is compound, on the two columns, like so:

CREATE TABLE `theTable` (
  `col_1` smallint(5) unsigned NOT NULL default '0',
  `col_2` smallint(5) unsigned NOT NULL default '0',
  PRIMARY KEY  (`col_1`,`col_2`)
) TYPE=MyISAM
[download]

12-million rows

Anyway - liked the direct comparison routine above, Jenda's suggestions, and the suggested re-write of the sql, and so I tried them all, like so:

    #method 1 - Perl intersection using @col arrays
    $sql = "SELECT col_2 FROM theTable WHERE col_1 = ?";
    $sth = $dbh->prepare($sql) or die("Could not prepare!" . $dbh->err
+str);
    $start_1 = new Benchmark;
    for $i (0 .. $iterations) {
        $sth->execute($value_1) or die("Could not execute 1!" . $dbh->
+errstr);
        while ($data = $sth->fetchrow_array()) {
            push(@col_1, $data);
        }
        $sth->execute($value_2) or die("Could not execute 2!" . $dbh->
+errstr);
        while ($data = $sth->fetchrow_array()) {
            push(@col_2, $data);
        }
        foreach $e (@col_1) { $union{$e} = 1 }
        foreach $e (@col_2) {
            if ( $union{$e} ) { $isect{$e} = 1 }
        }
        @isect = keys %isect;
    }
    $end_1 = new Benchmark;
    $diff = timediff($end_1, $start_1);

    #method 2 - Perl intersection using 'undef'
    $sql = "SELECT col_2 FROM theTable WHERE col_1 = ?";
    $sth = $dbh->prepare($sql) or die("Could not prepare!" . $dbh->err
+str);
    $start_2 = new Benchmark;
    for $i (0 .. $iterations) {
        $sth->execute($value_1) or die("Could not execute 1!" . $dbh->
+errstr);
        while ($data = $sth->fetchrow_array()) {
            $union{$data} = undef;
        }
        $sth->execute($value_2) or die("Could not execute 2!" . $dbh->
+errstr);
        while ($data = $sth->fetchrow_array()) {
            $isect{$data} = undef if exists $union{$data};
        }
        @isect = keys %isect;
    }
    $end_2 = new Benchmark;
    $diff = timediff($end_2, $start_2);

    #method 3 - MYSQL
    $sql = "SELECT COUNT(*) FROM theTable A JOIN responses B ON (A.col
+_2 = B.col_2) WHERE A.col_1 = ? AND B.col_1 = ?";
    $sth = $dbh->prepare($sql) or die("Could not prepare!" . $dbh->err
+str);
    $start_3 = new Benchmark;
    for $i (0 .. $iterations) {
        $sth->execute($value_1, $value_2) or die("Could not execute 1!
+" . $dbh->errstr);
    }
    $end_3 = new Benchmark;
    $diff = timediff($end_3, $start_3);
[download]

Result? For 100 iterations:

Method 1 - my original: 64 sec
Method 2 - modified sql & 'undef': 13 sec
Method 3 - SQL join: 15 sec

Pretty stable over ~10 repeats. I'm ultra impressed by the difference between 1 & 2.

But I'm jealous of the post above showing the same ~14 seconds for tens times as many iterations of the same query. What the heck?