Non-adherence to drug therapy has not been extensively studied in patients with chronic kidney disease (CKD). The objective of the present study was to identify determinants of non-adherence to drug therapy in patients with CKD, not on dialysis. A prospective cohort study involving 149 patients was conducted over a period of 12 months. Adherence to drug therapy was evaluated by the self-report method at baseline and at 12 months. Patients who knew the type of drug(s) and the respective number of prescribed pills in use at the visit preceding the interview were considered to be adherent. Patients with cognitive decline were assessed by interviewing their caregivers. Mean patient age was 51 ± 16.7 years. Male patients predominated (60.4%). Univariate analysis performed at baseline showed that non-adherence was associated with older age, more pills taken per day, worse renal function, presence of coronary artery disease, and reliance on caregivers for the administration of their medications. In multivariate analysis, the factors that were significantly associated with non-adherence were daily use of more than 5 pills and drug administration by a caregiver. Longitudinal evaluation showed an increase in non-adherence over time. Medication non-adherence was lower (17.4%) at the baseline period of the study than after 1 year of the study (26.8%). Compared to the baseline period, the percentage of adherent patients who became non-adherent (22%) was lower than the percentage of non-adherent patients who became adherent (50%). In CKD patients not on dialysis, non-adherence was significantly associated with the number of pills taken per day and drug administration by third parties. Adherence is more frequent than non-adherence over time.