I-81 crosses the Potomac River from West Virginia and enters Maryland as a four-lane freeway with a speed limit of . The Interstate curves to the northeast around Williamsport, where the highway meets MD 68 and MD 63 (Lappans Road) at a diamond interchange (Exit 1) to the south of the town and US 11 (Virginia Avenue) at a five-ramp partial cloverleaf interchange (Exit 2) to the east. Beyond US 11, I-81's speed limit drops to . The Interstate passes along the edge of the Hagerstown suburb of Halfway, where the highway meets I-70 (Eisenhower Memorial Highway) at a cloverleaf interchange (Exit 4) with collector-distributor lanes on both I-81 and I-70. Traffic for I-68 is advised to use I-70 west. I-81 meets Halfway Boulevard, which leads to several shopping centers including the Valley Mall, at a six-ramp partial cloverleaf interchange (Exit 5).