RATIONALE & OBJECTIVE: Increasing evidence has linked ambient fine particulate matter (ie, particulate matter no larger than 2.5 μm [PM(2.5)]) to chronic kidney disease (CKD), but their association has not been fully elucidated, especially in regions with high levels of PM(2.5) pollution. This study aimed to investigate the long-term association of high PM(2.5) exposure with incident CKD in mainland China. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 72,425 participants (age ≥18 years) without CKD were recruited from 121 counties in Hunan Province, China. EXPOSURE: Annual mean PM(2.5) concentration at the residence of each participant derived from a long-term, full-coverage, high-resolution (1 × 1 km(2)), high-quality dataset of ground-level air pollutants in China. OUTCOMES: Incident CKD during the interval between the baseline examination of each participant (2005-2017) and the end of follow-up through 2018. ANALYTICAL APPROACH: Cox proportional hazards models were used to estimate the independent association of PM(2.5) with incident CKD and the joint association of PM(2.5) with temperature or humidity on the development of PM(2.5)-related CKD. Restricted cubic splines were used to model exposure-response relationships. RESULTS: Over a median follow-up of 3.79 (IQR, 2.03-5.48) years, a total of 2,188 participants with incident CKD were identified. PM(2.5) exposure was associated with incident CKD with an adjusted hazard ratio of 1.71 (95% CI, 1.58-1.85) per 10-μg/m(3) greater long-term exposure. Multiplicative interactions between PM(2.5) and humidity or temperature on incident CKD were detected (all P < 0.001 for interaction), whereas an additive interaction was detected only for humidity (relative risk due to interaction, 3.59 [95% CI, 0.97-6.21]). LIMITATIONS: Lack of information on participants' activity patterns such as time spent outdoors. CONCLUSIONS: Greater long-term ambient PM(2.5) pollution is associated with incident CKD in environments with high PM(2.5) exposure. Ambient humidity has a potentially synergetic effect on the association of PM(2.5) with the development of CKD. PLAIN-LANGUAGE SUMMARY: Exposure to a form of air pollution known as fine particulate matter (ie, particulate matter ≤2.5 μm [PM(2.5)]) has been linked to an increased risk of chronic kidney disease (CKD), but little is known about how PM(2.5) affects CKD in regions with extremely high levels of PM(2.5) pollution. This longitudinal cohort study in China investigates the effect of PM(2.5) on the incidence of CKD and whether temperature or humidity interact with PM(2.5). Our findings suggest that long-term exposure to high levels of ambient PM(2.5) significantly increased the risk of CKD in mainland China, especially in terms of cumulative average PM(2.5). The associations of PM(2.5) and incident CKD were greater in high-humidity environments. These findings support the recommendation that reducing PM(2.5) pollution should be a priority to decrease the burden of associated health risks, including CKD.