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To investigate how the relationship of infant weight gain with adolescent body mass index (BMI) differs for individuals born during and before the obesity epidemic era.Data from two British birth cohorts, the 1946 National Survey of Health and Development (NSHD, n=4199) and the 2001 Millennium Cohort Study (MCS, n=9417), were used to estimate and compare associations of infant weight gain between ages 0 and 3 years with adolescent outcomes.BMI Z-scores and overweight/obesity at ages 11 and 14 years.Infant weight gain, in Z-scores, was positively associated with adolescent BMI Z-scores in both cohorts. Non-linearity in the MCS meant that associations were only stronger than in the NSHD when infant weight gain was above −1 Z-score. Using decomposition analysis, between-cohort differences in association accounted for 20%–30% of the differences (secular increases) in BMI Z-scores, although the underlying estimates were not precise with 95% CIs crossing 0. Conversely, between-cohort differences in the distribution of infant weight gain accounted for approximately 9% of the differences (secular increases) in BMI Z-scores, and the underlying estimates were precise with 95% CI not crossing 0. Relative to normal weight gain (change of −0.67 to +0.67 Z-scores between ages 0 and 3 years), very rapid infant weight gain (>1.34), but not rapid weight gain (+0.67 to +1.34), was associated with higher BMI Z-scores more strongly in the MCS (β=0.790; 95% CI 0.717 to 0.862 at age 11 years) than in the NSHD (0.573; 0.466 to 0.681) (p<0.001 for between-cohort difference). The relationship of slow infant weight gain (<−0.67) with lower adolescent BMI was also stronger in the MCS. Very rapid or slow infant weight gain was not, however, more strongly associated with increased risk of adolescent overweight/obesity or thinness, respectively, in the more recently born cohort.Greater infant weight gain, at the middle/upper end of the distribution, was more strongly associated with higher adolescent BMI among individuals born during (compared with before) the obesity epidemic. Combined with a secular change towards greater infant weight gain, these results suggest that there are likely to be associated negative consequences for population-level health and well-being in the future, unless effective interventions are developed and implemented.