就网友的这个例句来看，不宜（不是不能）换成in。简单说来，一般的语法书上说at用于小地方，in用于大地方，只不过这个大和小，不是客观标准，而是说话人的主观看法（说话人认为是大地方，就会用in；说话人认为是小地方，就会用at），而网友提供的这个例句，在地点house前面有个词little，所以不宜换成in，这也是这句话的作者为什么用at而没有用in的原因。

一家之言，仅供参考；勤查英英，必有所获！

我认为把in和at用法以地点大小来区分，是不准确的。国内的中小学老师习惯上按大小来分，这是过于简单化了，也是一个误区。at 强调是某个点，而不是其他的点。in表示在某个空间内，可以指一个地方。这个地方可大可小。因此你的句子完全可以替换为in his little house. 请看外媒带有little house的例句：

1.He was murdered one hot summer night in his little house in Islington.

2. He had rewarded her all spring and summer, each fall setting her ashore to remain in his little house in Boston the rest of the year, to learn her lessons and wait impatiently for his return in April.

3. How proud he was when invited by Hudig to stay with him at his little house in the country.

4. One day when Tyler was in his room at his little house in the country enjoying his toys guess what?

特别请网友体会句4： room 小 却用in, house 大却用了at. 足以证明两个介词的用法不能简单地用地点大小来区分。