Three Vietnamese visitors died when the homemade device ripped through the bus after it was concealed behind a wall, officials said.
The Egyptian tour guide who had accompanied them was killed in the explosion at 6.15pm local time (4.45pm GMT) while the driver, also Egyptian, was injured.
Another 10 of the 14 tourists from Vietnam were hurt in the explosion while only one without physical injuries.
Pictures from the scene showed the side of the bus ravaged by the explosion, near the country's historic landmarks.
Officials said the bus was travelling in the Marioutiyah area near the pyramids on Friday when the roadside bomb went off.
The improvised explosive device was placed near a wall along a street, officials said this evening.
Security services were immediately dispatched to the area and have opened an investigation into the explosion.
No group immediately claimed responsibility for the attack and it was not clear whether the vehicle had struck the bomb or whether it was launched from the side of the road.
Egypt has battled Islamic militants for years in the Sinai Peninsula in an insurgency that has occasionally spilled over to the mainland, hitting minority Christians or tourists.
However, this is the first attack to target foreign tourists in almost two years.
Western tourists have been warned of the dangers, with Britain's Foreign and Commonwealth Office advising that an attack in Egypt was 'very likely'. READ MORE
