We are planning our honeymoon for November of this year and think we have decided on South Africa.

We are thinking of taking 3 weeks, and so far our itinerary includes several days in Cape Town, 2-3 days in the winelands, a few along the Garden Route, and two game reserves -- Kwandwe and Madikwe. We originally had been thinking about an island add-on (Mauritius or Seychelles), but now are considering other options, as well. Any suggestions for other additions to our itinerary (either within SA or in another region)? One caveat is that we prefer to be in malaria-free areas for specific health-related reasons. Thanks in advance for any and all suggestions!

I have never heard of the Kwandwe Game Reserve, so cannot comment on that, but Madikwe is a good choice. You rule out the Kruger Park and the northern part of KwaZulu-Natal (malaria) so the other regions that I would suggest you consider are:
The Kgalkgadi Transfrontier Park,
The Drakensberg (North, Central or South - they are all great)
The Wild Coast of the Transkei
Good Luck - and Congratulations.
Rudi

South part of Kruger is Malaria free - though we even went up the northen part in February and I never saw one mosquito

The entire Kruger Park is in a malaria area. So too is the rest of the Mpumalanga and Limpopo lowveld. And in November, being summer, the risk is higher than in mid-year.

How about Madikwe Hills or Mateya?...both Maleria free and they get excellent reviews for both accommodations and animal sightings.