This marks San Filippo's third visit to the National Qualifying Tournament. He missed qualifying for the Champions Tour by one stroke at last year's event in Orlando.
After making a 15-foot birdie putt at the 10th hole to move to 4 under, San Filippo capped his round with consecutive birdies at Nos. 16, 17 and 18.
Bob Cameron and Brad Bryant each fired 6-under 66's on Wednesday and trail San Filippo by one stroke. R.W. Eaks, Tony Peterson, Tom McKnight and Hajime Meshiai are all two shots back.
Jim Ahern finished his first round at 2 under par, while Mark Hayes and Dick Mast each shot 1-under 71. Lon Hinkle, Dave Barr and Rick Rhoden ended at even par. Stewart Ginn was 1 over par for the day, while Howard Twitty (plus-2) and Bob Duval (plus-5) also struggled.
Only seven players will walk away with full exemptions for next year on the Champions Tour, and just eight more will receive conditional status.
For the first time, the tournament will be contested over 108 holes. The field will be cut after four rounds to the low 70 and ties, plus any additional players who remain within 10 shots of the 15th position.
The six-day event concludes on Monday, November 22nd.