TCP Handshake
The three-way SYN / SYN-ACK / ACK exchange that establishes a TCP connection, costing one round trip before any data moves.
One round trip before the first byte of a request, plus one or two more for TLS. On a 200 ms path that is 400–600 ms of pure setup, which is why connection reuse matters far more than most application optimisation.
The consequences worth designing around: HTTP keep-alive and connection pooling eliminate the handshake on subsequent requests; a client that opens a fresh connection per request pays it every time, and no application profiler will show you why. TCP Fast Open can carry data in the SYN for repeat connections, though support is patchy.
Related: congestion control ramps up after the handshake, so a short-lived connection never reaches full throughput. Two reasons pooling wins, not one.