Background <p>Proteinuria is often assessed by a single measurement, but persistent proteinuria has seldom been studied. Therefore, we investigated its association with cigarette smoking.</p> Methods <p>We prospectively followed 9,220 middle-aged Japanese men without renal dysfunction, proteinuria, diabetes, antihypertensive treatment, or cancer at baseline. Smoking status, daily cigarette consumption, and pack-years were assessed by questionnaire. Participants were grouped as nonsmokers, past smokers, or current smokers. Current smokers were classified by daily consumption (1–20 or ≥ 21) and cumulative exposure (0.1–40.0 or ≥ 40.1 pack-years). Persistent proteinuria was defined as proteinuria detected at ≥ 3 consecutive annual examinations. We used Cox proportional hazards models.</p> Results <p>There were 1972 nonsmokers, 2007 past smokers, and 5241 current smokers. During the 11-year follow-up, persistent proteinuria developed in 181 participants (28, 30, and 123 in each group), corresponding to incidence rates of 1.6, 1.7, and 2.6 per 1,000 person-years, respectively. In multivariate models, current smoking, daily cigarette consumption, and cumulative smoking consumption were significantly associated with the risk of persistent proteinuria, compared with nonsmoking. For daily cigarette consumption, multiple-adjusted HRs of persistent proteinuria for those who smoked 1−20, and ≥ 21 cigarettes per day were 1.59 (95% CI, 1.01−2.50), and 1.83 (1.15−2.91), respectively (P for trend = 0.011). For cumulative smoking exposure, the corresponding HRs for those with a pack-year of 0.1− 40.0, and ≥ 40.1 were 1.56 (1.00 −2.41), and 2.09 (1.26 −3.45), respectively (P for trend = 0.003).</p> Conclusions <p>In middle-aged Japanese men, cigarette smoking was associated with persistent proteinuria, and the risk rose with daily and cumulative smoking.</p>