PURPOSE: To obtain the titled substance in high selectivity in high yield, by carrying out a reaction of an isobutylene source and a formaldehyde source in a low-temperature reaction zone charged with a cation exchange resin first, followed by doing it in a high-temperature reaction zone wherein the reaction solution is treated at high temperature.

CONSTITUTION: At least one isobutylene source selected from isobutylene, tertiary butanol and an alkyl tertiary butyl ether and a formaldehyde source together with water and a water-soluble acidic catalyst are fed to a low-temperature reaction zone packed with a cation exchange resin catalyst and reacted at 30W115°C, preferably at 50W110°C, to synthesize an isoprene precursor. The reaction solution introduced from the low-temperature zone, containing a water-soluble acidic catalyst, is fed to a high-temperature zone, subjected to the latter stage reaction at ≥120°C, preferably 130W210°C, so that the precursor is decomposed to give isoprene. The amount of isobutylene is preferably ≤20mol based on 1mol formaldehyde.