South Africa were 227 for three when rain ended play half an hour early - 102 runs behind the West Indian first innings total of 329.
On a day of largely attritional cricket, the West Indies opted for defensive fields after an initial burst of aggression with the new ball, while the South African batsmen were content to keep the scoreboard ticking over.
A near-capacity crowd then saw Amla and De Villiers forge a careful unbeaten fourth wicket partnership of 70. Amla made 55 not out off 130 balls with seven fours, while De Villiers was on 32 off 52 deliveries, hitting four boundaries.
Fast bowlers Dale Steyn and Morne Morkel took two wickets each as South Africa wrapped up the West Indian first innings inside the first hour.
Jerome Blackwood reached his third Test half-century with a cover drive for four off Steyn but was then trapped in front of his stumps with a full, swinging delivery after making top score of 56.
Jason Holder and Jerome Taylor both went for their shots before perishing to mistimed blows. Holder top-edged a pull and was caught at mid-on and Taylor was caught at fine leg when he hooked a ball from Morkel.
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