Drug addiction is increasingly viewed as the expression of abnormal associative learning following repeated exposures to the drugs of abuse. Previous studies have demonstrated that the patterns of repetition such as frequency and spacing are important to many kinds of learning and memory retention. We hypothesized that drug repetition pattern might affect the reward-related learning although the total doses of the drug were the same. In the present study, we tested morphine-induced place preference following either regular or irregular pattern of morphine pairing in rats. Regular morphine group received morphine administration daily at a regular time with the same dose. Irregular morphine groups received morphine administration either at the same time but irregular doses, irregular time but same dose, or irregular time and irregular doses. We found that rats, who received irregular morphine pairing, exhibited similar acquisition of place preference but different preference retentions compared with regular morphine-treated rats after the same total dose of morphine. Rats, who received morphine administration at the same time but irregular doses and at irregular time and irregular doses, showed rapid disruption of place preference than the regular morphine group. Rats, who received morphine at irregular time but the same dose, showed similar retention of place preference to regular morphine group. Our results suggest that the pattern of drug pairing plays an important role in the retention of reward-related memory. This study may provide new evidence to broaden our understanding of the development and maintenance of drug craving.