<b><i>Introduction:</i></b> Guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the first line of treatment for insomnia in general practice, but CBT-I is rarely available. Nurse-guided Internet-delivered CBT-I might be a solution to improve access to care. <b><i>Objective:</i></b> We aimed to determine the effectiveness of nurse-guided Internet-delivered CBT-I (I-CBT-I) on insomnia severity experienced by patients in general practice. <b><i>Methods:</i></b> Nurse-guided I-CBT-I (“i-Sleep”) was compared to care-as-usual (and I-CBT-I after 6 months) in 15 participating general practices among 134 patients (≥18 years old) with clinical insomnia symptoms. Assessments took place at 8, 26 and 52 weeks. Primary outcome was self-reported insomnia severity (Insomnia Severity Index) at 8 weeks. Secondary outcomes were sleep diary indices, depression and anxiety symptoms (Hospital Anxiety and Depression Scale), fatigue, daytime consequences of insomnia, sleep medication and adverse events. <b><i>Results:</i></b> Two thirds of the 69 intervention patients (<i>n</i> = 47; 68%) completed the whole intervention. At the posttest examination, there were large significant effects for insomnia severity (Cohen’s <i>d =</i>1.66), several sleep diary variables (wake after sleep onset, number of awakenings, terminal wakefulness, sleep efficiency, sleep quality) and depression. At 26 weeks there were still significant effects on insomnia severity (<i>d</i> = 1.02) and on total sleep time and sleep efficiency. No significant effects were observed for anxiety, fatigue, daily functioning or sleep medication. No adverse events were reported. <b><i>Conclusions:</i></b> Nurse-guided I-CBT-I effectively reduces insomnia severity among general practice patients. I-CBT-I enables general practitioners to offer effective insomnia care in accordance with the clinical guidelines.