The next number in the sequence 3, 9, 27, 81 is 243. This sequence is a geometric progression where each term is multiplied by 3 to get the next term. Starting from 3:

• 3 × 3 = 9
• 9 × 3 = 27
• 27 × 3 = 81
• 81 × 3 = 243

So, the next number after 81 is 243.