<p><b>BACKGROUND: </b>The association between accelerometer-assessed physical activity and risk of diabetes remains unclear, especially among US Hispanic/Latino adults who have lower levels of physical activity and a higher diabetes burden compared with other racial/ethnical populations in the country.</p><p><b>OBJECTIVES: </b>To examine the association between accelerometer-assessed physical activity and incident diabetes in a US Hispanic/Latino population.</p><p><b>METHODS: </b>We included 7280 participants of the Hispanic Community Health Study/Study of Latinos who aged 18-74 y and free of diabetes at baseline. Data on moderate-to-vigorous physical activity (MVPA) were collected using a 7-d accelerometer measurement. Incident diabetes was assessed after a mean ± SD of 6.0 ± 0.8 y using standard procedures including blood tests. RRs and 95% CIs of diabetes associated with MVPA were estimated using survey Poisson regressions. The associations of MVPA with 6-y changes in adiposity measures were also examined.</p><p><b>RESULTS: </b>A total of 871 incident cases of diabetes were identified. MVPA was inversely and nonlinearly associated with risk of diabetes (P-nonlinearity = 0.006), with benefits accruing rapidly at the lower end of MVPA range (<30 min/d) and leveling off thereafter. The association differed by population age (P-interaction = 0.006). Higher MVPA was associated with lower risk of diabetes among individuals older than 50 y (RRQ4 versus Q1 = 0.50; 95% CI: 0.35, 0.73; P-trend < 0.001) but not among younger individuals (RRQ4 versus Q1 = 0.98; 95% CI: 0.66, 1.47; P-trend = 0.92). An inverse association between MVPA and 6-y gain in waist circumference was also limited to the older group (P-interaction with age < 0.001).</p><p><b>CONCLUSIONS: </b>Among US Hispanic/Latino adults, baseline accelerometer-derived MVPA was inversely associated with incident diabetes only among individuals aged 50 y and older. Further studies are needed to confirm our findings and to clarify potential mechanisms underlying the possible age differences in the MVPA-diabetes association. This study was registered at clinicaltrials.gov as NCT02060344.</p>