Widespread adoption of intrathecal morphine into clinical practice is hampered by concerns about its potential side-effects. We undertook a systematic review, meta-analysis and trial sequential analysis with the primary objective of determining the efficacy and safety of intrathecal morphine. Our secondary objective was to determine the dose associated with greatest efficacy and safety. We also assessed the impact of intrathecal morphine on respiratory depression. We systematically searched the literature for trials comparing intrathecal morphine with a control group in patients undergoing hip or knee arthroplasty under spinal anaesthesia. Our primary efficacy outcome was rest pain score (0–10) at 8–12 hours; our primary safety outcome was the rate of postoperative nausea and vomiting within 24 hours. Twenty-nine trials including 1814 patients were identified. Rest pain score at 8–12 hours was significantly reduced in the intrathecal morphine group, with a mean difference (95%CI) of −1.7 (−2.0 to −1.3), p < 0.0001 (19 trials; 1420 patients; high-quality evidence), without sub-group differences between doses (p = 0.35). Intrathecal morphine increased postoperative nausea and vomiting, with a risk ratio (95%CI) of 1.4 (1.3–1.6), p < 0.0001 (24 trials; 1603 patients; high-quality evidence). However, a sub-group analysis by dose revealed that rates of postoperative nausea and vomiting within 24 hours were similar between groups at a dose of 100 µg, while the risk significantly increased with larger doses (p value for sub-group difference = 0.02). Patients receiving intrathecal morphine were no more likely to have respiratory depression, the risk ratio (95%CI) being 0.9 (0.5–1.7), p = 0.78 (16 trials; 1173 patients; high-quality evidence). In conclusion, there is good evidence that intrathecal morphine provides effective analgesia after lower limb arthroplasty, without an increased risk of respiratory depression, but at the expense of an increased rate of postoperative nausea and vomiting. A dose of 100 µg is a ‘ceiling’ dose for analgesia and a threshold dose for increased rate of postoperative nausea and vomiting.