I would say that testing is required but it is nice to know other peoples experiences. In my experience on ms sql server, nulls can and do cause massive performance issues (differences). In a very simple test now I have seen a query return in 45 seconds when not null was set on the related fields in the table create statement and over 25 minutes where it wasn't set (I gave up waiting and just took a peak at the estimated query plan).
Test data is 1 million rows x 20 columns which are constructed from 62 random lowercase alpha characters on an i5-3320 normal HD and 8GB RAM (SQL Server using 2GB) / SQL Server 2012 Enterprise Edition on windows 8.1. It's important to use random data / irregular data to make the testing a realistic "worse" case. In both cases table was recreated and reloaded with random data that took about 30 seconds on database files that already had a suitable amount of free space.
select count(field0) from myTable where field0
not in (select field1 from myTable) 1000000
CREATE TABLE [dbo].[myTable]([Field0] [nvarchar](64) , ...
vs
CREATE TABLE [dbo].[myTable]([Field0] [nvarchar](64) not null,
for performance reasons both had table option data_compression = page set and everything else was defaulted. No indexes.
alter table myTable rebuild partition = all with (data_compression = page);
Not having nulls is a requirement for in memory optimized tables for which I am not specifically using however sql server will obviously do what is fastest which in this specific case appears to be massively in favor of not having nulls in data and using not null on the table create.
Any subsequent queries of the same form on this table return in two seconds so I would assume standard default statistics and possibly having the (1.3GB) table fit into memory are working well.
i.e.
select count(field19) from myTable where field19
not in (select field18 from myTable) 1000000
On an aside not having nulls and not having to deal with null cases also makes queries much simplier, shorter, less error prone and very normally faster. If at all possible, best to avoid nulls generally on ms sql server at least unless they are explicitly required and can not reasonably be worked out of the solution.
Starting with a new table and sizing this up to 10m rows / 13GB same query takes 12 minutes which is very respectable considering the hardware and no indexes in use. For info query was completely IO bound with IO hovering between 20MB/s to 60MB/s. A repeat of the same query took 9 mins.