Water-related health challenges on First Nations reserves in Canada have been previously documented. Our objective was to describe factors associated with self-reported health effects from tap water in 8 First Nations reserve communities in Saskatchewan, Canada. Community-based participatory approaches were used in designing and implementing cross-sectional household surveys. Individual, household, community, and contextual effects were considered in multilevel analysis. Negative health effects from tap water were reported by 28% of households (n = 579). Concerns about environmental factors affecting water quality (odds ratio [OR] = 3.4, 95% confidence interval [CI] = 1.8-6.7), rarely or never drinking tap water (OR = 2.9, 95% CI = 1.3-6.6), insufficient tap water (OR = 3.0, 95% CI = 1.4-6.3), paying for bottled water (OR = 3.2, 95% CI = 1.2-8.7), and dissatisfaction with tap water were associated with self-reported health effects (n = 393); however, the effect of dissatisfaction was modified by respondent age ( P = .03). Quality and availability were associated with perceptions of health effects from drinking water, providing additional information on how ongoing concerns about drinking water influence self-reported health in some First Nations.