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To the authors’ knowledge, no prospective studies have examined adverse drug reaction (ADR) occurrence among older adults attending general practice. In this study, ADRs were found to occur for approximately one in four older adults over a 6-year period. Cardiovascular, nervous system, and anti-infective drugs for systemic use were the most commonly implicated drug classes. Approximately one in four ADRs rated as moderate resulted in additional healthcare utilisation. Female sex, polypharmacy (5–9 drug classes), and major polypharmacy (≥10 drug classes) increased the likelihood of ADRs.