Suppose the table's layout is as follows:

    CREATE TABLE mytable
    (
        id int not null auto_increment,
        col1 datetime,
        col2 datetime,
        primary key (id)
    );

You may want to try one of two things

#IDEA #1 : Create a column to store difference in seconds

Create the column and populate as follows

    ALTER TABLE mytable ADD COLUMN dtdiff INT NOT NULL;
    ALTER TABLE mytable ADD INDEX (dtdiff);
    UPDATE mytable SET dtdiff = UNIX_TIMESTAMP(col1) - UNIX_TIMESTAMP(col2)l

If your table does not have foreign keys or constraints, do this instead:

    CREATE TABLE mytable_new LIKE mytable;
    ALTER TABLE mytable_new ADD COLUMN dtdiff INT NOT NULL;
    ALTER TABLE mytable_new ADD INDEX (dtdiff);
    INSERT INTO mytable_new
        SELECT id,col1,col2,
        UNIX_TIMESTAMP(col1) - UNIX_TIMESTAMP(col2)
        FROM mytable
    ;
    ALTER TABLE mytable RENAME mytable_old;
    ALTER TABLE mytable_new RENAME mytable;
    DROP TABLE mytable_old;

Once done, your query would essentially 

- `SELECT * FROM mytable WHERE dtdiff > 0` for `col1 > col2`
- `SELECT * FROM mytable WHERE dtdiff < 0` for `col1 < col2`

#IDEA #2 : Create a separate table to store difference in seconds

    CREATE TABLE mytable_dtdiff
    (
        id int not null,
        dtdiff int not null,
        primary key (id),
        key dtdiff (dtdiff)
    );
    INSERT INTO mytable_dtdiff
    SELECT id,UNIX_TIMESTAMP(col1) - UNIX_TIMESTAMP(col2)
    FROM mytable;

Once done, your query would essentially 

    SELECT B.* FROM
    (SELECT id FROM mytable_dtdiff WHERE dtdiff > 0) A
    LEFT JOIN mytable B USING (id);

for `col1 > col2` and

    SELECT B.* FROM
    (SELECT id FROM mytable_dtdiff WHERE dtdiff < 0) A
    LEFT JOIN mytable B USING (id);

for `col1 < col2`

Give it a Try !!!