Looking on the internet deeply has found these results:

What do you think the main problem is? is the most popular phrase on the web.

What do you think is the main problem? 1137,000 results on the web	What do you think the main problem is? 1918,000 results on the web More popular!
Some examples and use cases from the internet:	Some examples and use cases from the internet:
That is the main problem at this time. Oral ingestion via food, primarily fish, is the main problem relating to mercury in Europe. That is the main problem in the motor industry. When to start is the main problem. The industry structure is the main problem for lacking competition, as barriers to entry are very high. Indeed, it is the lack of transparency that is the main problem. That is the main problem we have to combat. So what is the main problem?	But what do you think the problem is? Why do you think the main character commits suicide? What do you think the problem is? What do you think the problem is? And What Do You Think The Problem Is? What do you think the gravestone really is? What do you think the problem is? AND WHAT DO YOU THINK THE PROBLEM IS?

What do you think is the main problem?

1137,000 results on the web

What do you think the main problem is?

1918,000 results on the web

More popular!

That is the main problem at this time.
Oral ingestion via food, primarily fish, is the main problem relating to mercury in Europe.
That is the main problem in the motor industry.
When to start is the main problem.
The industry structure is the main problem for lacking competition, as barriers to entry are very high.
Indeed, it is the lack of transparency that is the main problem.
That is the main problem we have to combat.
So what is the main problem?