It should work just fine to decode the file line by line.  "Proof":

#!/usr/bin/perl

use MIME::Base64 ();

my $file_name = shift @ARGV;
my $buf;

open my $fh_in,  "<", $file_name or die $!;
open my $fh_out, ">", $file_name.".base64" or die $!;

while (read($fh_in, $buf, 100*57)) {
    print $fh_out MIME::Base64::encode($buf);
}
close $fh_out;

open my $fh_base64,  "<", $file_name.".base64"  or die $!;
open my $fh_decoded, ">", $file_name.".decoded" or die $!;

while ($buf = <$fh_base64>) {
    print $fh_decoded MIME::Base64::decode($buf);
}
__END__
$ ./757820.pl hugefile
$ ls -l hugefile*
-rw-r--r-- 1 almut almut 618119168 2009-02-07 02:01 hugefile
-rw-r--r-- 1 almut almut 835003088 2009-04-16 04:51 hugefile.base64
-rw-r--r-- 1 almut almut 618119168 2009-04-16 04:51 hugefile.decoded
$ cmp hugefile hugefile.decoded
$
[download]

Do you maybe have some junk around the actual base64 data section in your encoded file, or is it maybe additionally transfer-encoded one way or another (e.g. quoted-printable)?