Leaders Narberth go on the road face Bonymaen, which means a quick return to Parc Mawr for Otters full back Adrian Killa, who played at scrum half for Bony last season.
Pontypool, in second place after defeating Aberavon on Saturday, will have a difficult match at Pandy Park, Tondu, where the home side are always difficult to beat.
Pontypool, like Naberth, have won all their four matches so far, but will be without skipper Mark Jones, who is out with a broken arm.
Cross Keys, also unbeaten after three wins and a draw, will have a tough task as they meet fellow Gwent club Tredegar, who are another tough club to beat at home.
Bedwas, after impressive wins at Carmarthen and Newbridge, will entertain Llandovery in what should be an entertaining match at Central Park, while Rumney will be hoping to record their first win of the season as they play host to Beddau for the first time in a league meeting.
Whitland meet Llanharan, who have already won twice under their new coach Dennis John, and Carmarthen Quins should overcome an improving Treorchy side.
Aberavon coach Chris O'Callaghan will be keen to see the Wizards back on the winning trail at home to Glamorgan Wanderers and Blackwood meet Newbridge in what is likely to be a keenly-contested local derby.
Divison 1 Fixtures. 24th Septemeber
Aberavon v Glamorgan Wanderers;
Bedwas v Llandovery;
Blackwood v Newbridge;
Bonymaen v Narberth;
Carmarthen Quins v Treorchy;
Rumney v Beddau;
Tondu v Pontypool;
Tredegar v Cross Keys;
Whitland v Llanharan.
A special video package as Pontypridd claimed the double for the first time in their history by winning the Principality Premiership final, including match build-up, highlights, post match reaction and dressing room celebrations.