Both Lloyd Williams and Rhys Patchell have failed to recover from the injuries they picked up in the 28-8 victory over Newport Gwent Dragons and are replaced by Lewis Jones and Aled Summerhill.
Up front Matthew Rees gets the nod ahead of Kristian Dacey while Josh Navidi comes in at number eight, with Josh Turnbull moving into second-row and Jarrad Hoeata dropping to the bench.
Head coach Danny Wilson said: "Unfortunately Lloyd and Rhys have not recovered in time for this weekend but we have had a good week of training and are looking forward to Judgement Day,
"It should be a really exciting game at the Principality Stadium in front of more than 65,000 fans."
Wales' Capital Region must beat the Ospreys and then Edinburgh in the final round of the PRO12 season to give themselves the best chance of a top six finish.
That would secure a spot in the top tier European Champions Cup and while they have lost their last nine encounters against the Ospreys, Wilson is optimistic.
Wilson added: "It's another derby and we have prepared for every one previously as a massive fixture and are not looking any further.
"We have won four from five derbies so far this season and it would be great to make it five from six with a win against the Ospreys."
Cardiff Blues: 15 Dan Fish, 14 Aled Summerhill, 13 Garyn Smith, 12 Rey Lee-Lo, 11 Tom James, 10 Gareth Anscombe, 9 Lewis Jones; 1 Gethin Jenkins (c), 2 Matthew Rees, 3 Taufa'ao Filise, 4 Josh Turnbull, 5 James Down, 6 Sam Warburton, 7 Ellis Jenkins, 8 Josh Navidi
Replacements: 16 Kristian Dacey, 17 Brad Thyer, 18 Dillon Lewis, 19 Jarrad Hoeata, 20 Manoa Vosawai, 21 Tomos Williams, 22 Jarrod Evans, 23 Gavin Evans
Guinness PRO12 Blues News
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