Chronic pain is one of the most common conditions for which people seek treatment with cannabis-based medicinal products (CBMPs) and there is mounting real world evidence that CBMPs are safe and effective in treating pain. Many people with chronic pain also experience major depression and it is unknown whether pain patients with major depression derive equal benefit from CBMPs as those who are not depressed since comorbidities are usually an exclusion factor in RCTs. This study aimed to investigate whether patients with chronic pain with and without co-morbid depression experience the same improvement in pain and quality of life outcomes after three months of medical cannabis treatment. Data were derived from Project Twenty21 (T21), one of the largest observational studies in medicinal cannabis in the UK. Baseline data were available for 1816 chronic pain patients and three-month follow-up data were available for 1058 of these patients. Logistic regression models were used to examine the relationship between chronic pain and comorbid depression after three months of medical cannabis treatment controlling for sociodemographic factors. Prescribed cannabis was associated with marked reductions in pain severity and interference and with improvements in aspects of general health and quality of life. A substantial portion (23.4%) of chronic pain patients reported comorbid depression. Patients with comorbid depression reported more pain interference at baseline (mean = 7.5 vs 6.8, p < 0.01) while there was no significant difference for pain severity (mean = 5.9 vs 6.0, p > 0.05). Depression status did not predict reduction in pain severity and interference at three months, while baseline scores, age and number of total comorbidities predicted some treatment outcomes. These results indicate that comorbid depression should not be a barrier to accessing treatment with CBMPs for chronic pain patients.